Platinum Compounds Of Malonic Acid Derivative Having Leaving Group Containing Amino Or Alkylamino

ABSTRACT

Disclosed are a class of platinum compounds of malonic acid derivatives having a leaving group containing an amino or alkylamino, and pharmaceutically acceptable salt thereof, preparation method thereof and pharmaceutical composition containing the compounds. Also disclosed are uses of the compounds for treating cell proliferative diseases especially cancers. The platinum compounds of the present invention have high solubility in water, low toxicity and strong anti-tumor effect.

FIELD OF THE INVENTION

The invention relates a category of platinum containing compounds fortreating cell proliferative diseases, and in particular relates a sensesof platinum containing compounds with the leaving group of malonic acidderivatives containing amino and alkyl amino radical, preparationmethods and uses thereof.

BACKGROUND OF THE INVENTION

Cancers (malignant tumor) are among the leading diseases threatening thehuman life today. The morbidity and mortality of cancers have increasedsharply in recent years. The tumor development trend revealed by theWorld Health Organization (WHO) indicates that, the annual global newlyconfirmed tumor patients are more than 10, 000, 000 since 1996. As inthe end of 1999, the global total tumor patients have exceeded 40, 000,000. Approximately 7, 000, 000 persons die of various cancers all aroundthe world each year. In 2001, the world morbidity and mortality of tumorhave increased by 22% from 1990. Cancer has become the second main causeof death just next to cardiovascular and cerebrovascular diseases. Themost common cancers are lung cancer, breast cancer, colorectal cancer,gastric cancer, liver cancer, cervical cancer, esophageal cancer, andbladder cancer. The authoritative survey data on the morbidity andmortality of cancers in China in 2006 published on the tenth NationalClinical Oncology Conference show that the cancer deaths are 3, 000, 000in China in 2006. There are approximately 2, 120, 000 newly confirmedcancer patients each year. In the mortality of malignant tumor, lungcancer ranks the first of malignant tumor. Experts estimated that, by2020, the death toll will exceed 4, 000, 000; by 2025, tumor will becomethe first major cause for global death toll.

There are three means for clinically treating cancers: operation,radiotherapy and chemotherapy. Antitumor drugs are the most commonlyused way of the treatment. In 2008, the global market sale of antitumordrugs is US$ 48 billion. At present, clinical antitumor drugs are mainlyclassified into alkylating agent, antimetabolites, metal platinum, plantalkaloids and other crude drugs, cytotoxic antibiotics, etc. Platinumantitumor drugs are sort of principal antitumor drugs and cisplatin wasfirstly developed in 1960s. The important difference from traditionalcytotoxic antitumor drugs is their unique mechanism of action andexcellent selectivity. The major target is DNA, which is cross-linkedinter and intra DNAs and forms platinum complex˜DNA complex, to disturbDNA replication or combine with nucleoprotein and plasmosin, belongingto cell cycle nonspecific agent (CCNSA). Cis-dichlorodiamminoplatinumi.e., Cisplatin, cis-1,1-cyclobutanedicarboxylate platinum, i.e.,Carboplatin, cis-glycolic acid-diammineplatinum i.e., Nedaplatin,oxalate-(trans-L-1,2-cyclohexanediamine) platinum i.e., Oxaliplatin,cis-[(4R,5R)-4,5-bi-(aminomethyl)-2-isopropyl 1,3-dioxanel(bidentate)platinum, i.e., Sunpla, and 1,2 diaminomethyl-cyclobutane-lactateplatinum i.e., Lobaplatin etc. have been successfully developed insuccession. Platinum antitumor drugs are characterized by wide antitumorspectrum, good effect, etc. Moreover, they are well collaborated withother antitumor drugs. This not only improves the inhabitation ratio ofthe existed tumor, but also expands antitumor spectrum, thusconsolidating the position of platinum antitumor drugs in clinicaltreatment. In the ranking among hundreds of antitumor drugs conducted byWHO in 1995, cisplatin ranks the second in the comprehensive evaluationon curative effect and market. Statistical data indicate that, among allchemotherapy regimens in China, more than 70%-80% are dominated byplatinum or compatible with platinum drugs.

Platinum antitumor drugs, however, now with high toxicity, has manydefects, including bone marrow suppression, nephrotoxicity, nerveinjury, etc., poor solubility, comparatively narrow anticancer spectrum,drug resistance, etc. Therefore, designing and synthesizing new platinumantitumor drugs remains one of the leading directions for the presentantitumor drug research (M. A. Jakuper, M. Galanski, B. K. Keppler.Tumor-inhibiting platinum complexes-state of art and futureperspectives, Rev. Physiol Biochem Pharmacol, 2003, 146, 1-53).

Substantive studies have been conducted in recent two years to reducethe toxic and side effects of platinum chemotherapy drug, improvecurative effect, reduce tumor recurrence and avoid drug resistance, andimprove the water solubility of platinum compound. For example, thesolubility of cisplatin is 2.65 mg/ml. Later the solubility ofOxaliplatin is 7.9 mg/ml; the solubility of Carboplatin is 17.8 mg/ml;that of Minoplatin is 27 mg/ml. Comparing with cisplatin, the toxic andside effects of Oxaliplatin and Carboplatin are reduced. The deficiencyis that the solubility of above so called water-soluble platinumcompounds remain slight soluble or sparingly soluble. Murray A. Plan etal prepared the sodium alcoholate salt for platinum compound,effectively improved the solubility externally (U.S. Pat. No.4,322,362A), but the compound must be dissolved under the conditionabove pH10 and the toxicity has still not been effectively solved.Giulia C et al also prepared series of platinum compounds. However, thesolubility of those compounds was still not remarkably improved (ChemMed Chem, 2009, 4(10), 1677-1685). WO2006091790A1 also made public aseries of platinum compounds with specific structure, but similarly, thesolubility was still not distinctively improved.

SUMMARY OF THE INVENTION

The present invention provides a class of platinum compounds used forthe treatment of proliferating diseases, in particular platinumcompounds with the leaving group of malonic acid derivative containingamino and alkylamino radical, their pharmaceutical acceptable salts,solvates, stereoisomers or their prodrugs. Comparing with the existingplatinum antitumor drugs, the aqueous solubility of the compounds in theinvention has been greatly improved, and the toxicility and side effectshave been significantly reduced, and unexpected technical effects havebeen produced. The compounds are showed in formula A:

Wherein:

R₀ may or may not exist. When R₀ exist, it is selected from alkyl,naphthenic base, alkoxy alkyl, alkyl amino alkyl, heterocycle, alkenyland chain alkynyl, which are unsubstituted; or optionally substituted byhalogen, hydroxyl, alkoxy, alkyl, alkoxy alkyl, naphthenic base,heterocycle, aryl, provided that R₀ do not contain unsaturated bond, orR₀ contains unsaturated bond, while the atom of the unsaturated bondcannot be directly connected with nitrogen atom; and then formula A isquaternary ammonium base, while when R₀ does not exist, formula A istertiary amine base;R₁ and R₂ may be the same or different, selected from hydrogen, alkyl,naphthenic base, alkoxy alkyl, alkyl amino alkyl, heterocycle, alkenyl,chain alkynyl which are unsubstituted; or optionally substituted byhalogen, hydroxyl, alkoxy, alkyl, alkoxy alkyl, naphthenic base,heterocycle, aryl, provided that R₁ or R₂ do not contain unsaturatedbond, or R₁ and/or R₂ contains unsaturated bond, while the atom of theunsaturated bond cannot be directly connected with nitrogen atom;R₁, R₂ and the atoms connected with them may form a closed saturated orunsaturated heterocycle. For example, it can be ternary, quaternary,pentabasic, hexahydric, heptabasic or octatomic ring; the above ringsmay be optionally condensed with other rings and may be optionallysubstituted by halogen, hydroxyl, alkoxy, alkyl, alkoxy alkyl,naphthenic base, heterocycle, aryl, provided that the atom connectedwith nitrogen atom is saturated carbon atom;R₃ is the straight chain alkyl or the naphthenic base of C₄ and it canbe substituted by one or more alkoxy, hydroxyl, alkyl, halogen,halogenated alkyl, alkoxy alkyl, heterocycle; of which, the abovementioned alkoxy may include but not limited to methoxyl, oxethyl,propoxy, and isopropoxy; the above mentioned alkyl may include but notlimited to methyl, ethyl and isopropyl.R₄ and R₅ may be the same or different, selected from: hydrogen,hydroxyl, alkyl, naphthenic base, alkoxy, alkoxy alkyl, heterocycle,alkenyl, chain alkynyl; wherein alkyl, alkenyl, chain alkynyl,naphthenic base, alkoxy alkyl, alkyl amino alkyl and heterocycle areunsubstituted or optionally substituted, preferably substituted byhalogen, hydroxyl, alkoxy, straight chain or branched-chain alkyl,alkoxy alkyl, naphthenic base or heterocycle;R₄, R₅ and the atoms connected with them may form a closed ring. Forexample, the closed ring may be quaternary, pentabasic, hexahydric,heptabasic or octatomic ring; the above rings may be optionallycondensed with other rings and may be optionally substituted.

Preferably, R₀ does not exist or R₀ is selected from C₁₋₈ alkyl,naphthenic base, alkoxy alkyl, alkyl amino alkyl, or heterocycle; R₁ andR₂ are selected from hydrogen, C₁₋₈ alkyl, naphthenic base, alkoxyalkyl, alkyl amino alkyl, or heterocycle; R₃ may be but not limited toC₄ alkyl or C₄ naphthenic base; R₄ and R₅ are selected from hydrogen,hydroxyl, C₁₋₈ alkyl, naphthenic base, alkoxy, alkoxy alkyl, andheterocycle.

More preferably, the present invention provides compounds of formula Band their pharmaceutically acceptable salts:

Wherein R₀, R₁, R₂, R₃ are as described above.

Most preferably, R₀ does not exist, and R₁ and R₂ are hydrogen, methyl,ethyl or propyl, or heterocycle formed by R₁, R₂ and N, for example: thequaternary, pentabasic, hexahydric, or heptabasic heterocycle containingN with saturated or unsaturated bond; R₃ is ethyl or propyl.

The present invention further provides compounds of formula C and theirpharmaceutically acceptable salts, solvates, stereoisomers or theirprodrugs, i.e. the compounds obtained when R₄, R₅ and their connectedatoms forming a closed ring together. The structural formula C is asfollows:

Wherein, the group where R₁, R₂, R₃ are selected from is describedabove,

is preferable but not limited to the groups below:

The groups above may also be optionally connected with variousappropriate substituted groups.

The platinum complex in formula C, wherein R₆ may be but not limited to(CH₂)_(n), wherein n=1-6, preferably 3-5, the most preferably 4; whereinfor some —CH₂— may be substituted by —O—. One or more hydrogens of(CH₂)_(n) may be substituted by halogen, alkyl, hydroxyl or alkoxy, etc.The preferably compound is selected from (±) trans-1,2-cyclohexanediamine platinum (II), (±) trans-1,2-cyclopentamethylene diamineplatinum (II), (±) trans-1,2-cyclobutanediamine platinum (II) and (±)trans-1,2-cyclopropane diamine platinum (II);

R₇ may be but not limited to (CH₂)_(n), wherein n=0-3, preferably n=0-2;wherein some —CH₂— may be substituted by —O—, and one or more hydrogenof (CH₂)_(n) may be substituted by halogen, alkyl, hydroxyl,hydroxyalkyl or alkoxy, etc.;R₈ and R₉ may be but not limited to hydrogen, halogen, hydroxyl,hydroxyalkyl, alkyl, alkoxy, heterocycle, etc. R₈ and R₉ may be the sameor different, preferably hydroxymethyl (F);R₁₀ and R₁₁ may be but not limited to hydrogen, halogen, hydroxyalkyl,alkyl, alkoxy, heterocycle, etc. R₁₀ and R₁₁ may be the same ordifferent, preferably hydroxymethyl;R₁₂ may be but not limited to (CH₂)_(n), wherein n=2-4, wherein some—CH₂— may be substituted by —O—. One or more hydrogen of (CH₂)_(n) maybe substituted by halogen, alkyl, hydroxyl or alkoxy, etc.;R₁₃ may be —CH₂— or —O—, preferably —CH₂—;R₁₄ may be hydrogen, halogen, alkyl, alkoxy, hydroxyalkyl or hydroxyl.R₁₄ is preferably hydrogen;R₁₅ may be but not limited to (CH₂)_(n), wherein n=1-3, —CH₂—O— or —O—;wherein one or more hydrogens of (CH₂)_(n) may be substituted by alkyl,alkoxy, hydroxyl, or hydroxyalkyl; preferably —CH₂—O—CH₂—.

Preferably, the base structure of compound is as follows:

The most preferably compounds in this invention include:

-   Compound 1: 2-(4-diethylamino butyl)-malonato.Cis-diamine    platinum(II) acetate;-   Compound 2: 2-(4-diethylamino    butyl)-malonato.Cis-(1,2-ethylenediamine) platinum (II) tosilate;-   Compound 3: 2-(4-diethylamino    butyl)-malonato.Cis-(1,2-trans-cyclohexanediamine) platinum (II)    tosilate;-   Compound 4: 2-(4-(1-piperidyl)-butyl)-malonato.Cis-diamino    platinum (II) phosphate;-   Compound 5: 2-(4-(1-tetrahydropyrrolo)-butyl)-malonato.Cis-diamine    platinum (II) phosphate;-   Compound 6: 2-(3-dimethylamino cyclobutyl)-malonato.Cis-diamine    platinum (II) mesylate;-   Compound 7: 2-(4-di-n-propylamino butyl)-malonato.Cis-diamine    platinum (II) phosphate;-   Compound 8: 2-(3-methyl-4-diethylamino butyl)-malonato.Cis-diamine    platinum (II) acetate;-   Compound 9:    2-(4-(1-piperidyl)-butyl)-malonato.Cis-(1,2-trans-cyclohexanediamine)    platinum (II) tosilate;-   Compound 10:    2-(4-(2-methyl-1-tetrahydropyrrolo)-butyl)-malonato.Cis-diamine    platinum (II) phosphate;-   Compound 11:    2-(4-aminobutyl)-malonato.Cis-(1,2trans-cyclohexanediamine)    platinum (II) phosphate;-   Compound 12: 2-(4-ethylamino    butyl)-malonato.Cis-(1,2-trans-cyclohexanediamine) platinum (II)    phosphate;-   Compound 13:    2-(4-N-methyl-isopropyl-aminobutyl)-malonato.Cis-(1,2-trans-cyclohexanediamine)    platinum (II) acetate;-   Compound 14: 2-(4-diethylamino    butyl)-malonato.Cis-(1,2-trans-cyclopentane diamine) platinum (II)    phosphate;-   Compound 15: 2-(4-diethylamino    butyl)-malonato.Cis-(1,2-trans-cyclobutanediamine) platinum (II)    succinate;-   Compound 16: 2-(4-diethylamino    butyl)-malonato.Cis-(1,2-trans-cyclopropanediamine) platinum (II)    phosphate;-   Compound 17: 2-(4-diethylamino    butyl)-malonato.Cis-(1,2-ethylenediamine) platinum (II) tosilate;-   Compound 18: 2-(4-diethylamino butyl)-malonato.Cis-(1,3-propane    diamine) platinum (II) phosphate;-   Compound 19: 2-(4-diethylamino    butyl)-malonato.Cis-(1,4-butanediamine) platinum (II) phosphate;-   Compound 20: 2-(2-diethylamino butyl)-malonato.Cis-1,2-(1,2-bis    hydroxymethyl)-ethylene diamine platinum (II) phosphate;-   Compound 21: 2-(4-diethylamino    butyl)-malonato.Cis-1,3-(2,2-hydroxymethyl)-propane diamine    platinum (II) phosphate;-   Compound 22: 2-(4-diethylamino    butyl)-malonato.Cis-1,4-(trans-2,3-cyclobutyl)-butanediamine    platinum (II) phosphate;-   Compound 23: 2-(4-diethylamino butyl)-malonato.Cis-(1,4-cyclohexyl    diamine) platinum (II) phosphate;-   Compound 24: 2-(4-diethylamino    butyl)-malonato.Cis-1,3-(2,2-(4-oxacycloalkylhexyl))-propane diamine    platinum (II) phosphate;-   Compound 25: 2-(4-diethylamino    butyl)-malonato.Cis-dicyclopentylamine platinum (II) acetate;-   Compound 26: 2-(4-diethylamino    butyl)-malonato.Cis-.ammonia.cyclopentylamine platinum (II) acetate;-   Compound 27: 2-(4-diethylamino    butyl)-malonato.Cis-.(2-aminomethyl-cyclopentylamine) platinum (II)    acetate;-   Compound 28: 2-(4-diethylamino butyl)-malonato.Cis-.ammonia    piperidine platinum (II) acetate;-   Compound 29: 2-(4-trimetlylamino    butyl)-malonato.Cis-(1,2-trans-cyclohexanediamine) platinum (II)    tosilate.

The following are the definitions of various terms used in thedescription of the present invention. Unless limited in special case,the following terms are applicable to the entire description and claims(independently or as a part of larger group).

The term “alkyl” refers to straight chain or branched-chain univalentsaturated alkyl. To be specific, alkyl refers to the straight chainunivalent saturated alkyl with 1-20 (C₁₋₂₀), 1-15 (C₁₋₁₅), 1-10 (C₁₋₁₀),1-7(C₁₋₇) or 1-4(C₁₋₄) carbon atoms, or the branched chain saturatedalkyl with 3-20(C₃₋₂₀), 3-15 (C₃₋₁₅), 3-10 (C₃₋₁₀), 3-7(C₃₋₇) or3-4(C₃₋₄) carbon atoms.

The examples of alkyl can be but not limited to methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, amyl (including allisomers), hexyl (including all isomers), heptyl (including all isomers),capryl group (including all isomers), nonyl (including all isomers),decyl (including all isomers), hendecyl (including all isomers), dodecyl(including all isomers), tridecyl (including all isomers), myristyl(including all isomers), pentadecyl (including all isomers), hexadecyl(including all isomers), heptadecyl (including all isomers), octadecyl(including all isomers), nonadecyl (including all isomers) and eicosyl(including all isomers). For example, C₁₋₇ alkyl refers to the straightchain univalent saturated alkyl with 1-7 carbon atoms or the branchedchain univalent saturated alkyl with 3-7 carbon atoms.

“Alkyl” may be substituted by one, two, three or four of the followingsubstituent groups: such as halogen, trifluoromethyl, trifluoromethoxyl,hydroxyl, alkoxy, cycloalkyloxy, heterocyclic oxygroup, oxo, alkaneacyl, aryloxy, alkane acyl oxygen radical, amino, alkylamino, arylamino,aralkyl amido, naphthene amido, heterocyclic amido, substituent tertiaryamine (wherein 2 nitrogen substituent groups are selected from alkyl,aryl or aralkyl); alkane acyl amido, aroyl amino, aryl alkane acylamido, substituent alkane acyl amido, substituent aromatic amino,substituent aryl alkane acyl, thiodiglycolic, alkyl sulfonium, arylsulfonium, aralkyl sulfonium, naphthenic sulfonium, heterocyclicsulfonium, alkyl carbonyl sulfur, aryl carbonyl sulfur, aromatic alkylcarbonyl sulfur, alkyl sulfonyl, aryl sulfonyl, aromatic alkyl sulfonyl,sulfonamide (such as SO₂NH₂), substituted sulfonamide, nitryl, cyano,carboxyl, carbamyl (such as CONH₂), substituted carbamyl (such as CONHalkyl, CONH aryl, CONH aralkyl or when two substituent groups exist onnitrogen, selected from alkyl, aryl or aralkyl); alkoxy carbonyl, aryl,substituent aryl, guanidyl and heterocyclic radical (such as indolyl,imidazolyl, furyl, thienyl, thiazolyl, pyrrolidyl, pyridyl, pyrimidyl,etc.). The above substituted groups may be further substituted byhalogen, alkyl, alkoxy, aryl or aralkyl.

The term “alkoxy” refers to the group generated by the connection ofstraight chain univalent saturated alkyl with 1-20(C₁₋₂₀), 1-15 (C₁₋₁₅),1-10 (C₁₋₁₀), 1-7(C₁₋₇) or 1-4(C₁₋₄) carbon atoms or branched chainsaturated alkyl with 3-20(C₃₋₂₀), 3-15(C₃₋₁₅), 3-10 (C₃₋₁₀), 3-7(C₃₋₇)or 3-4(C₃₋₄) carbon atoms and oxygen atoms. The examples of alkoxy canbe but not limited to methoxyl, ethyoxyl, propoxy, isopropoxy, N-botuxy,isobutoxy, sec-butoxy, tert-butoxy, pentyloxy (including all isomers),hexyloxy (including all isomers), heptyloxy (including all isomers),octyloxy (including all isomers), nonyloxy (including all isomers),decyloxy (including all isomers), Undecyl alkoxy (including allisomers), Dodecyl alkoxy (including all isomers), tridecyl alkoxy(including all isomers), tetradecyl alkoxy (including all isomers),pentadecyl alkoxy (including all isomers), hexadecyl alkoxy (includingall isomers), heptadecylalkoxy (including all isomers), octadecylalkoxy(including all isomers), nonadecanxyalkoxy (including all isomers) andeicosantl alkoxy (including all isomers).

The term “alkylamino” refers to base groups which one or two H in —NH₂are substituted by straight chain alkyl with 1-10 (C₁₋₁₀), 1-6 (C₁₋₆) or1-4(C₁₋₄) carbon atoms or branched chain alkyl with 3-10(C₃₋₁₀),3-6(C₃₋₆) or 3-4(C₃₋₄) carbon atoms respectively; When the two H aresubstituted at the same time, the substituent groups can be the same ordifferent. The examples of alkylamino can be but not limited tomethylamino, dimethylamino, ethylamino, diethylamino, propylamino,dipropylamino, isopropylamino, diisopropylamide, N-butylamino,Iso-butylamino, Tert-butylamino, Di-n-butylamino, Di-iso-butylamino,Di-tert-butylamino, Amylamino, Di-Amylamine, hexylamino, Di-hexylamino,heptamino, Di-heptamino, octamino, Di-octamino, nonoamino, di-nonoamino,decamino, di-decamino, N-methyl-N-ethylamino, N-methyl-N-propylamino,N-methyl-N-isopropylamino, N-methyl-N-butylamino,N-methyl-N-isobutylamino, N-methyl-N-tertbutylamino,N-methyl-N-amylamino, N-methyl-N-hexylamino, N-methyl-N-heptylamino,N-methyl-N-octylamino, N-methyl-N-nonylamino, N-methyl-N-decylamino,N-ethyl-N-propylamino, N-ethyl-N-isopropylamino, N-ethyl-N-butylamino,N-ethyl-N-isobutylamino, N-ethyl-N-Tert-butylamino, N-ethyl-N-amylamino,N-ethyl-N-hexylamino, N-ethyl-N-heptylamino, N-ethyl-N-octylamino,N-ethyl-N-nonylamino, N-ethyl-N-decylamino, N-Propyl-N-isopropylamino,N-Propyl-N-butylamino, N-Propyl-N-isobutylamino,N-Propyl-N-Tert-butylamino, N-Propyl-N-amylamino, N-Propyl-N-hexylamino,N-Propyl-N-heptylamino, N-Propyl-N-octylamino, N-Propyl-N-nonylamino,N-propyl-N-decylamino, N-isopropyl-N-butylamino,N-isopropyl-N-isobutylamino, N-isopropyl-N-tertbutylamino,N-isopropyl-N-pentylamino, N-isopropyl-N-hexylamino,N-isopropyl-N-heptylamino, N-isopropyl-N-octylamino,N-isopropyl-N-nonylamino, N-isopropyl-N-decylamino,N-butyl-N-isobutylamino, N-butyl-N-tertbutylamino,N-butyl-N-pentylamino, N-butyl-N-hexylamino, N-butyl-N-heptylamino,N-butyl-N-octylamino, N-butyl-N-nonylamino, N-butyl-N-decylamino,N-isobutyl-N-tertbutylamino, N-isobutyl-N-pentylamino,N-isobutyl-N-hexylamino, N-isobutyl-N-heptylamino,N-isobutyl-N-octylamino, N-isobutyl-N-nonylamino,N-isobutyl-N-decylamino, N-tert-butyl-N-pentylamino,N-tert-butyl-N-hexylamino, N-tert-butyl-N-heptylamido,N-tert-butyl-N-octylamino, N-tert-butyl-N-decylamino,N-tert-butyl-N-decylamino, N-amyl-N-hexylamino, N-amyl-N-heptylamido,N-amyl-N-octylamino, N-amyl-N-nonylamino, N-amyl-N-decylamino,N-hexyl-N-heptylamido, N-hexyl-N-octylamino, N-hexyl-N-nonylamino,N-hexyl-N-decylamino, N-heptyl-N-octylamino, N-heptyl-N-nonylamino,N-heptyl-N-decylamino, N-octyl-N-nonylamino, N-octyl-N-decylamino,N-nonyl-N-decylamino and also include all isomers thereof.

The term “halogen” or “halogenate” refers to fluorine, chlorine,bromine, and iodine.

The term “aryl” refers to monocyclic or dicyclic aromatics containing6-12 carbon atoms, such as phenyl, naphthyl, biphenyl and diphenyl. Theabove “aryl” may be substituted.

“Aryl” may be substituted by any of the following substituent groups:such as alkyl, halogen, trifluoromethoxy, trifluoromethyl, hydroxyl,alkoxy, cycloalkyloxy, heterocyclic oxygroup, alkane acyl, alkane acyloxygen radical, amino, alkylamino, aralkyl amido, naphthene amido,heterocyclic amido, dialkyl amino, alkane acyl amido, thiol, alkylsulfo, naphthenic base sulfo, heterocycle sulfo, carbamido, nitryl,cyano, carboxyl, carboxyl alkyl, formamyl, alkoxy carbonyl, alkylcarbonyl sulfur, aryl carbonyl sulfur, alkyl sulfonyl, sulfonamido,aryloxy, etc. The said substituent groups may be further substituted byhalogen, hydroxyl, alkyl, alkoxy, aryl, substituent aryl, substituentalkyl or aralkyl.

The term “aralkyl” refers to the aryl combined directly through alkylgroup, such as benzyl, phenethyl and phenylpropyl.

The term “alkenyl” refers to the straight chain or branched-chain alkylgroup with one, two, three or four ethylenic bonds containing 2-20carbon atoms, preferably 2-15 carbon atoms, most preferably 2-8 carbonatoms and it includes but not limited to vinyl, N-allylnormetazocine,isopropenyl, n-butyl-2-alkenyl, and hexanoic-3-alkenyl. The term alsoincludes groups with cis-form and trans-form structure or E and Zstructure. The technicians in this field can understand.

“Alkenyl” may be substituted by any of the following substituent groups,such as halogen, hydroxyl, alkoxy, alkane acyl, alkane acyl oxygenradical, amino, alkylamino, dialkyl amino, alkanoyl amido,thiodiglycolic, alkyl sulfo, alkyl carbonyl sulfur, alkyl sulfonyl,sulfonamido, nitryl, cyano, carboxyl, formamyl, substituted formamyl,guanidyl and heterocyclic radical, such as indolyl, imidazolyl, furyl,thienyl, thiazolyl, pyrrolidyl, pyridyl, and pyrimidyl, etc.

The term “alkynyl” or “chain alkynyl” refers to the straight chain orbranched chain alkyl group with 1-4 acetylenic bonds containing 2-20carbon atoms, preferably 2-15 carbon atoms, most preferably 2-8 carbonatoms. It includes but not limited to ethynyl, n-propyl alkynyl,n-butyl-2-alkenyl, hexanoic-3-alkenyl, etc.

“Alkenyl” may be substituted by any of the following substituent groups:halogen, hydroxyl, alkoxy, alkane acyl, alkane acyl oxygen radical,amino, alkylamino, dialkyl amino, alkane acyl amido, thiodiglycolic,alkyl sulfo, alkyl carbonyl sulfur, alkyl sulfonyl, sulfonamido, nitryl,cyano, carboxyl, formamyl, substituted formyl amino, guanidyl andheterocyclic radical, such as imidazolyl, furyl, thienyl, thiazolyl,pyrrolidyl, pyridyl, and pyrimidyl, etc.

The term “naphthenic base” refers to optionally substitutive, saturatehydrocarbon ring system preferably containing 1-3 rings and each (may befurther condensed with unsaturated C₃-C₇ carbonatomic ring) containing3-7 carbon atoms. Example groups include cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, cyclo-octyl, cyclodecyl, cyclicdodecyl and adamantyl. Example for substituent group includes one ormore of alkyl groups as described above, or one or more of alkylsubstituent groups as described above.

The terms “heterocycle”, “heterocyclic” and “heterocyclic radical” referto optionally substituted, completely saturated or incompletelysaturated aromatic or non-aromatic ring group, for example, the saidring is 4-7-membered monocyclic, 7-11-membered dicyclic or10-15-membered tricyclic system, containing at least one heteroatom onthe ring at least containing on carbon atom. There may be 1, 2 and 3 or4 heteroatoms selected from nitrogen atom, oxygen atom and sulphur atomon each ring of heterocyclic group containing heteroatom, wherein thesaid nitrogen and sulphur heteroatom may also be optionally oxidized andnitrogen heteroatom may also be optionally quaternized. The saidheterocyclic group may be connected on any heteroatom or carbon atom.

Example monocyclic heterocyclic group includes pyrrolidyl, pyrryl,indolyl, pyrazolyl, oxa-cyclobutyl group, pyrazolinyl, imidazolyl,imidazolinyl, imidazolidinyl, oxazolyl, oxazolidinyl, isoxazolinyl,isoxazolyl, thiazolyl, thiadiazole, oxazolidinyl, isoxazolinyl,isoxazolyl, furyl, tetrahydrofuran, thienyl, oxadiazol, piperidyl,piperazinyl, 2-oxo-piperazinyl, 2-oxo-piperidyl, 2-oxo-pyrrolidyl,2-oxo-pazepine, azepine, 4-piperidone, pyridyl, N-oxo-pyridyl,pyrazinyl, pyrimidyl, pyridazinyl, tetrahydrothiopyran,tetrahydropyrane, morpholinyl, thiamethoxam morpholinyl, thiamethoxammorpholine sulfoxide, tetrahydrothiopyran sulfoxide, thiamethoxammorpholinyl sulfoxide, 1,3-dioxolame and tetralin-1,1-dioxo thienyl,dioxane, isoxazolyl, thia cyclobutyl, thia cyclopropyl, triazinyl andtriazolyl, etc.

Example bicyclic heterocyclic group includes benzothiazolyl,benzoxazolyl, benzothiophene, quinuclidinyl, quinolyl, quinolyl-N-oxide,tetrahydroisoquinol, isoquinolyl, benzimidazolyl, benzopyranyl,indolizine, benzopyranyl, chromone, aryl coumarin, 1,2-phthalazine,quinoxaline, indazolyl, pyrrolo and pyridyl, furan and pyridyl (such asfuran and [2,3-c]pyridyl, furan and [3,1-b]pyridyl or furan and[2,3-b]pyridyl), isoindolinyl, dihydrogen quinazoline (such as3,4-dihydro-4-oxo-quinazolinyl), benzisothiazol, benzisoxazole,benzodiazine, benzopyranyl, benzothiopyran, benzodiazine, benzofuryl,thiochroman, thiochroman sulphone, chroman, chroman sulphone,dihydrobenzene benzopyranyl, indolinyl, isobenzopyran, isoindolinyl,1,5-phthalazine, 2,3-phthalazine, 3,4-methylenedioxy benzyl, purine,pyridine-pyridy, quinazolinyl, tetralinquinolyl, thiophene-furan,thiophene-pyridine, thiophene-thienyl, etc.

Smaller heterocycles, such as epoxide and aziridine, are also included.

The term “heteroatom” includes oxygen, sulphur and nitrogen.

The term “pharmaceutically acceptable salt” includes the active compoundsalt prepared with relatively nontoxic acid or alkali on the basis ofthe specific substituent group existed on the compound as described inthis invention. When the compound in the invention contains relativelyacidic functional group, alkali addition salt can be obtained byenabling the compound in neutral form to contact sufficient necessarywith alkali directly or in appropriate inert solvent. Examples ofpharmaceutical acceptable inorganic alkali salt derivatives includealuminum, ammonium, calcium, copper, ferric iron, ferrous, lithium,magnesium, manganese, bivalent manganese, potassium, sodium, zinc, etc.Pharmaceutical acceptable organic base salt derivatives include primary,secondary and tertiary amine salts; they include substituent amine,cyclammonium, amine, etc., such as arginine, glycine betaine, caffeine,choline, N,N′-dibenzyl ethylenediamine, diethylamine, 2-diethylaminoacyl alcohol, 2-dimethyl aminoacyl alcohol, cholamine,ethylenediamine, N-ethyl morpholine, N-ethyl piperidine, glucosamine,glucamine, histidine, hydrabamine, isopropamide, lysine,methylglucosamine, morpholine, piperazine, piperidine, polyamino resin,procaine, purine, theobromine, triethylamine, trimethylamine,tripropylamine, tromethamine, etc. When the compound of the preventinvention contains relatively alkali functional group, acid additionsalt can be obtained by enabling the compound in neutral form to contactsufficient required acid directly or in appropriate inert solvent.Examples of pharmaceutical acceptable acid addition salts include saltsderivated from inorganic acid, such as nitrate, carbonate, bicarbonate,phosphate, hydrophosphate, dihydric phosphate, sulphate, bisulfate,phosphite, hydrochloride, hydrobromide, hydriodate, etc.; salt derivatedfrom relative nontoxic organic acid, for example, acetic acid, propionicacid, isobutyric acid, malonic, benzoic acid, succinic acid, subericacid, fumaric acid, mandelic acid, phthalic acid, benzenesulfonic acid,p-toluenesulfonic acid, citric acid, tartaric acid, methanesulfonicacid, etc.; and also include arginine acid, for example, arginine saltand organic acid such as glucuronic acid or galactonic acid salts;preferably nitrate, carbonate, bicarbonate, phosphate, hydrophosphate,dihydric phosphate, sulphate, bisulfate, phosphite, acetate, propionate,isobutyrate, malonate, benzoate, succinate, suberate, fumarate,mandelate, phthalate, benzene sulfonate, tosilate, citrate, tartrate,mesylate, arginine salt, glucuronate or galactose acid salt.

In some embodiments in this invention, the leaving group of compounds inthe present invention contains basic group(s) that may form salt withacid and platinum (II) complex salts are prepared with the method wellknown to the technical person in this field. For example, it may formmesylate, trifluoromethanesulfonic salt with lower alkyl sulfonic acid,such as methanesulfonic acid, trifluoromethanesulfonic acid, etc.; formtosilate, benzene sulfonate, camphosulfonate with arylsulphonate, suchas benzenesulfonic acid or p-toluenesulfonic acid, etc; form appropriatesalts with organic carboxylic acid, such as acetic acid, fumaric acid,tartaric acid, oxalate, maleic acid, malic acid, succinic acid, lacticacid or citric acid, etc.; may form glutamate or aspartate with arginineacid, such as glutamic acid or aspartic acid; form appropriate saltswith inorganic acid, such as nitric acid, carbonic acid, sulfuric acidor phosphoric acid, etc. The acid that may be used include organic acid,inorganic acid, etc.

The compounds of the present invention may be interconverted with theirsalt form through the conventional method in this field. For example,free bases can be obtained by separation in conventional way after thecontacting between salts and alkali or acid, or the form of salts can beobtained by separation in conventional way by adding acid or alkali tothe compounds. Some physical properties of the free bases, such as thesolubility in polar solvent, are different from various salt forms;however, for the purpose of the present invention, salts and thecompounds in parent form have the same antitumor effect.

In addition to the salt form, the present invention may provide thecompounds in the form of prodrug esters. The “prodrug(s)” of thecompounds as described in this invention refers to the compounds thatare prone to chemical change in physiological environment to obtain thecompounds of the present invention. In addition, prodrugs can beconverted into the compounds of the present invention with chemical orbiochemical methods in separation environment. For example, when placedin the transdermial patch reponsitory containing appropriate enzyme orchemical reagent, prodrugs may be slowly converted into the compounds ofthe present invention. Prodrugs are usually pharmacological inertcompounds before converting into active drugs; however, this situationis not necessary. Usually, the functional group required by the activityin drug is concealed with “precursor group” (as defined below),releasing functional group through conversion (such as cracking inspecific operating condition) and obtaining the “precursor part” ofactive drug and prodrug. Precursor part may be catalyzed or inducedthrough such as hydrolysis reaction, or through another actor (such asenzyme, light, acid or alkali) or change of physical or environmentalparameter (such as change of temperature) or exposing physical orenvironmental parameters for spontaneous cracking. Comparing withoperating environment, actor may be endogenic, for example, the enzymeexisted in the cell where prodrug is given or the acidic environment ofgastro or provided from external source.

“Precursor Group” refers to a sort of protective group that can convertdrug into prodrug when the functional group used in covering active drugforms “precursor part”. Precursor group is usually connected with thefunctional group of drug through bond. The said bond can be cracked inspecific condition. Therefore, precursor group is a part of precursorpart. The said precursor part is cracked in specific operating conditionand releases functional group. As a specific example, the amideprecursor part of the formula —NH—C(O)CH₃ contains precursor group—C(O)CH₃.

It is well known in the art that a wide variety of precursor groups andthe part of precursorssuitably conceal the functional group in activecompounds to obtain prodrugs. For example, hydroxyl functional group maybecome suphonate, ester (such as acetic acid ester or maleic acid ester)or carbonic acid ester precursor part by concealing. This precursor partmay be hydrolyzed in the body, to obtain hydroxyl. Carboxyl can becovered into ester (including methyl, ethyl, pivaloyl acyloxy methyl,silicyl ester and sulpho acid ester), amide or hydrazide precursor part.They can be hydrolyzed in body to obtain carboxyl. The present inventionincludes the known esters and acyls used for change of solubility orhydrolysis property in the field, used as controlled-release or prodrugpreparation. For one skilled in the art, the specific examples ofappropriate precursor groups and their appropriate precursor parts areobvious.

Some compounds of the present invention may exist in the form ofnon-solvation and solvation including hydration. “Solvate” refers to thecompound generated from the combination of solvent molecule with themolecule or ion of solute. Solvent may be organic compound, inorganiccompound or the mixture of both. Some examples of solvent include butnot limited to carbinol, N, N-dimethyl formamide, tetralin furan,dimethylsulfoxide, and water. Generally, solvent form is equivalent tonon-solvent form and included in the range of the present invention.Some compounds of the present invention may exist in the form ofpolymorph or smorphism. In general, for the assumed usage of the presentinvention, all physical forms are the same and included in the range ofthe present invention.

Some compounds of the present invention have asymmetric carbon atom(rotophore) or other chiral centers; their raceme, non-enantiomer,geometric isomer, regional isomer and individual isomer (such asseparated enantiomer) are included in the range of the presentinvention. Those isomers may be split or asymmetrically synthesized withconventional method to make isomer “optical pure”, i.e., not containingother isomers on the whole. For example, if particular enantiomer of thecompound of the present invention is required, pure required enantiomercan be obtained through asymmetric synthesis preparation or throughchiral auxiliaries derivatization, wherein splitting the mixture ofdiasteromer obtained and cracking the assistant group, or when themolecule contains alkali functional group such as amino or acidicfunctional group such as carboxyl, appropriate optical active acid oralkali may be used for forming asymmetric heterogeneous salt, thensplitting the non-enantiomer formed hereof through fractionalcrystallization or chromatographic process well-known in this field,finally pure enantiomer is recovered.

The compound of the present invention may contain the isotope of theatom in abnormal proportion in one or more atoms constituting thecompound. For example, the compound may be labeled with radioisotopesuch as tritium (³H), iodine-125 (¹²⁵I) or carbon-14 (¹⁴C). Regardlessof whether it has radioactivity or not, all isotope forms of thecompound of the present invention are all included in the range of thepresent invention.

Another purpose of the present invention is to provide the preparationmethods for the foregoing compounds.

I. The preparation method for the formula (A) and (B) (when R₄═R₅═NH₃,it is B, in other situations, it is A) is provided as follows:

-   -   (1) Potassium chloroplatinite was added into water and the        mixture was stirred at room temperature; potassium iodide was        added into above solution to react away from light in water bath        under nitrogen charging condition;    -   (2) R₄NH₂ was dissolved by water and added dropwise into the        reaction solution in (1); the mixture was reacted in water bath        condition;    -   (3) After cooling down the above reaction mixture below room        temperature, R₅NH₂ was dissolved by water and then added        dropwise to the reaction mixture (2) to react in water bath;        yellow deposit in large quantity was generated in the mixture;        after cooling down the mixture below room temperature; diiodo        diamine platinum (II) was obtained through suction filtration        and washing.    -   (4) Ag₂SO₄ was added in water and then stirred; the above diiodo        diamine platinum (II) was added into the reaction mixture and        then water was added; the mixture was stirred in water bath        condition away from light and nitrogen is charged; dihydrol        diamine platinum (II).sufate was obtained by suction filtration;    -   (5) Diethyl malonate and Br—R₃—Br were put into a flask. K₂CO₃        and tetrabutylammonium bromide were added into the flask, then        the mixture was stirred and heated; after removal of solid by        suction filtration and washing, collect the filtrate and wash        the organic layer, dry it, and decompress the distillation        solvent and collect the distillation;    -   (6) 2-Br—R₃-diethyl malonate was put into a flask, then        anhydrous K₂CO₃ was added in and stirred with acetonitrile;        R₁—NH—R₂ or R₁—N(R₀)—R₂ was added into reaction mixture; the        mixture was stirred and heated; After filtering out insoluble        substance of the mixture, the filtrate was pumped dry and        residue was dissolved in organic solvent and washed with aqueous        solution; after dry the organic layer, decompress and removal        the solvent, and the product was obtained by purification.    -   (7) Put the product obtained in (6) in a flask. NaOH solution        was added into the product and stirred at room temperature.    -   (8) After mixing the product in (7) with acid solution, the        product in above (4) was added, the mixture was heated to obtain        the platinum compound of the present invention.

The preferable preparation method is as follows:

-   -   (1) Potassium chloroplatinite was added into water and the        mixture was stirred to at room temperature; potassium iodide was        dissolved by water and then put it into above solution while        nitrogen is charged to react in water bath at 40˜60° C. for 30        min to 60 min away from light;    -   (2) R₄NH₂ was dissolved by water and added dropwise into the        reaction liquid in (1); the mixture was reacted in water bath at        40˜60° C. for 30 min to 60 min;    -   (3) Cooling down the reaction mixture below 20° C., R₅NH₂        aqueous solution was added dropwise into the reaction mixture        in (2) to react in water bath for 30˜60 min at 4060° C., yellow        deposit in large quantity was generated in the mixture. After        cooling down the reaction solution below 20° C., diiodo diamine        platinum (II) was obtained by suction filtration, washing with        water, anhydrous ethanol, and diethyl ether in turn.    -   (4) Ag₂SO₄ was added in water and then stirred; the above diiodo        diamine platinum (II) was added into the reaction mixture and        then water was added to react for 4 to 8 hours at 40˜60° C. away        from light and N₂ is charged; Dihydrol diamine platinum        (II).sulphate was obtained after suction filtration.    -   (5) Diethyl malonate and Br—R₃—Br were put into a flask. K₂CO₃        and tetrabutylammonium bromide were added into the flask, then        the mixture was stirred and heated in oil bath; after removal of        solid by suction filtration and washing with diethyl ether.        Collect the filtrate and wash the organic layer with water, dry        it, and decompress the distillation solvent to collect the        distillation with certain vacuo;    -   (6) 2-Br—R₃-diethyl malonate was put into three flasks, then        anhydrous K₂CO₃ was added in and stirred with acetonitrile;        R₁—NH—R₂ or R₁—N(R₀)—R₂ was added into reaction mixture; the        mixture was stirred and heated in oil bath; after filtering out        insoluble substance of the mixture, the filtrate was pumped dry        and then added ethyl acetate solution, and washed with saturate        NaCl aqueous solution, after dry the organic layer, decompress        by water pump and removal the solvent, and the product was        obtained by purification.    -   (7) Put the product obtained in (6) in a flask. NaOH solution        was added into the product and stirred at room temperature.    -   (8) After mixing the product in (7) with acid solution, the        product in above (4) was added, the mixture was heated to obtain        the platinum compound of the present invention.

II. The preparation method in formula (C) is as follows:

-   -   (1) Potassium chloroplatinite was added into water and the        mixture was stirred at room temperature; potassium iodide was        dissolved by water and then added into above solution to react        away from light in water bath under nitrogen charging condition;    -   (2) After Bidentate ammonia NH₂—X—NH₂ was dissolved by water,        then it was added dropwise into the reaction mixture obtained        in (1) to react in water bath, yellow deposit in large quantity        was generated in the mixture; after cooling down the mixture        below room temperature, bidentatediiodo diamine platinum (II)        was obtained by suction filtration and washing;    -   (3) Ag₂SO₄ was added in water and then stirred; the above diiodo        diamine platinum (II) was added into the reaction mixture and        then water was added; the mixture was stirred in water bath        condition away from light and N₂ is charged; dihydrol diamine        platinum (II).sulfate was obtained by suction filtration;    -   (4) Putting diethyl malonate, Br—R₃—Br, K₂CO₃ and        tetrabutylammonium bromide into a flask, the mixture was heated        and stirred; after removal of solid by suction and washing,        filtrate was washed and dried over MgSO4; distillate was        collected in vacuo after removal of solvent;    -   (5) Br—R₃-diethyl malonate was put into a flask, then anhydrous        K₂CO₃ was added in and stirred with acetonitrile; R₁—NH—R₂ or        R₁—N(R₀)—R₂ was added into reaction mixture; the mixture was        stirred and heated; After filtering out insoluble substance of        the mixture, the filtrate was pumped dry and residue was        dissolved in organic solvent and washed with aqueous solution;        after dry the organic layer, decompress and removal the solvent,        and the product was obtained by purification;    -   (6) Put the product obtained in (5) in a flask. NaOH solution        was added into the product and stirred at room temperature.    -   (7) After treating the product in (6) with acid solution, the        product in above (3) was added, the mixture was heated to obtain        the platinum compound of the present invention.

The Preferred preparation method is as follows:

-   -   (1) Potassium chloroplatinite was added into water and the        mixture was stirred to at room temperature; potassium iodide was        dissolved by water and then put it into above solution while        nitrogen is charged to react in water bath at 40˜60° C. for 30        min to 60 min away from light;    -   (2) After Bidentate ammonia NH₂—X—NH₂ was dissolved by water,        then it was added dropwise into the reaction mixture obtained        in (1) to react in water bath for 30 min to 60 min at 40˜60° C.,        yellow deposit in large quantity was generated in the mixture.        After cooling down the reaction solution below 20° C., diiodo        diamine platinum (II) was obtained by suction filtration,        washing with water, anhydrous ethanol, and diethyl ether in        turn. yellow deposit in great quantity was afforded; after        cooling down the mixture below room temperature, bidentatediiodo        diamine platinum (II) was obtained by suction filtration and        washing.    -   (3) Ag₂SO₄ was added in water and then stirred; the above diiodo        diamine platinum (II) was added into the reaction mixture and        then water was added to react for 4 to 8 hours at 40˜60° C. away        from light and N₂ is charged; Dihydrol diamine platinum        (II).sulphate was obtained after suction filtration.    -   (4) Diethyl malonate and Br—R₃—Br were put into a flask. K₂CO₃        and tetrabutylammonium bromide were added into the flask, then        the mixture was stirred and heated in oil bath; after removal of        solid by suction filtration and washing with diethyl ether.        Collect the filtrate and wash the organic layer with water, dry        it, and decompress the distillation solvent to collect the        distillation with certain vacuo;    -   (5) Br—R₃-diethyl malonate was put into three flasks, then        anhydrous K₂CO₃ was added in and stirred with acetonitrile;        R₁—NH—R₂ or R₁—N(R₀)—R₂ was added into reaction mixture; the        mixture was stirred and heated in oil bath; after filtering out        insoluble substance of the mixture, the filtrate was pumped dry        and then added ethyl acetate solution, and washed with saturate        NaCl aqueous solution, after dry the organic layer, decompress        by water pump and removal the solvent, and the product was        obtained by purification.    -   (6) Put the product obtained in (5) in a flask. NaOH solution        was added into the product and stirred at room temperature.    -   (7) After mixing the product in (6) with acid solution, the        product in above (3) was added, the mixture was heated to obtain        the platinum compound of the present invention.

The present invention also provides a pharmaceutical compositioncontaining above compound(s), its pharmaceutically acceptable salt,stereoisomer, prodrug or its solvate and pharmaceutical acceptablecarriers. The composition contains approximately 0.01%-100%, preferablyapproximately 0.1%-100%, more preferably approximately 1%-100%, mostpreferably approximately 20%-100% (in weight) of one or more compoundsof the present invention. The remaining part is composed of appropriatedrug carrier(s) and/or excipient(s). The known method in this field andappropriate carrier may be used to form composition containing thecompound of the present invention to match with administration route.

The quantity of the active compound in unit dose preparation may bebetween approximately 0.001 mg and 1000 mg, preferably betweenapproximately 0.01 mg and 500 mg, and more preferably betweenapproximately 1 mg and 100 mg, and most preferably between approximately10 mg and 50 mg.

The administration may, for example, be oral, local, intravenous,subcutaneous, percutaneous, transdermal, intramuscular, intra-articular,parenteral, intra-arterial, intradermal, intraventricular, encephalic,intraperitoneal, within damage, intranasal, rectum, vagina, suction orthrough implantation repository. The term “parenteral” used in presentinvention includes subcutaneous, intravenous, intramuscular,intra-articular, within synovial fluid, within breast bone, intrathecal,intrhepatic, within damaged position and intracranial injection ortarget controlled infusion, preferably giving composition intravenously.The preparation of the prevent invention may be designed asquick-acting, immediate-release or long-acting. In addition, thecompound may be administered locally other than in systemic way, such asgiving (such as injecting) sustained release preparation. In accordancewith the representative embodiment, the composites of the presentinvention may be prepared into the drug for mammal, preferably forhuman.

One or more composites containing in the prevent invention may be givenrepeatedly, for example, at least 2, 3, 4, 5, 6, 7, 8 or more times, orthe composites may be given through continuous infusion. The appropriatepositions of drug delivery include but not limited to blood vessel,muscle, skin, bronchus, intestines and stomach, anus, vagina, eye andear. The preparation may adopt liquid dosage form, freeze-dry powderform, solid or semisolid, such as solution, suspension, emulsion,tablet, pill, capsule, powder, suppository, retention enema, cream,ointment, lotion, gel, aerosol, etc., preferably, the simple unit dosageform for delivering accurate dose.

For parenteral drug delivery, the composite may be in the form ofsterile injection and aseptic packaging powder, preferably, preparinginjection at pH value of approximately 4.5-8.0.

The composite of the present invention in sterile injection form arewater or oil mixed suspension. Such suspension may be prepared withsuitable dispersive or wetting agent and suspending agent according tothe known technology in the field. Sterile injection preparation may bethe sterile injection solution or suspension dissolved or suspended innontoxic parenteral acceptable diluent or solvent, such as the solutiondissolved in 1,3-butylene-glycol. Usable acceptable menstruum andsolvent include water, Ringer's solution and other hypertonic sodiumchloride solution. Additionally, sterile non-volatile oil is usuallyused as solvent or suspended substrate. Therefore, the nonvolatile oilof any brand including synthetic monoglyceride or diester can be used,similar to naturally pharmaceutical acceptable oil such as olive oil orcastor oil, especially their polyethylene oxide ethylation form. Fattyacid such as oleic acid and its glyceride derivant can be used toprepare injection preparation. Such oil solution or suspension may alsocontain long-chain alcohol diluent or dispersing agent, such ascarboxymethylcellulose or similar dispersing agent generally used in thepreparation in pharmaceutical acceptance dosage form including emulsionand suspension. Other commonly used surfactants, such as Tween, Span,and the acceptable solid, liquid usually used for preparation pharmacyor other emulsifier or bioavailability promoter in other dosage form maybe used for the purpose of preparation. Such compounds as those used forparenteral drug delivery, for example, through injection such as largedose injection or continuous infusion, may be prepared. Injection unitdosage form may be stored in ampoule or multiple-dose container.

The composites of the present invention in the form of freeze-drying maybe provided. Such composites may include buffer agent used forredissolution before drug delivery, or freeze-drying composites maycontain buffer agent, used for, for example, water redissolution.Freeze-drying composites may contain appropriate vasoconstrictor, suchas epinephrine. Freeze-drying composites may be delivered throughsyringe, optionally packaged with the buffer agent used forredissolution, for the convenience to immediately delivering suchredissolution composites to patients.

The medicinal composites of the present invention may also be used asany oral acceptable dosage form. They include tablet, capsule, cachet,emulsion, suspension, solution, syrup, elixir, spray, pill, lozenge,powder, granule and sustained release preparation. Appropriateexcipients used for oral administration include medical Mannitol,lactose, starch, magnesium stearate, saccharin sodium, lcum powder,cellulose, glucose, gelatin, cane sugar, magnesium carbonate, etc. Incase of the tablet used for oral administration, the common carriersinclude lactose and corn starch. Generally, lubricant such as magnesiumstearate may be added. In case of capsule, usable diluents includelactose and dry corn starch. When water suspension is required for oralmedication, active ingredient shall be mixed with emulsified andsuspending agents. Some sweetening agents, corrigents or colorants maybe added according to the circumstances.

One or more compounds of the present invention and optionally one ormore pharmaceutical acceptance auxiliary materials may be dissolved ordispersed on carriers such as salt aqueous solution, glucose aqueoussolution, glycerol, ethanol, etc. to form, for example, oral, local orintravenous administered solution or suspension for preparing liquidcompositions. Sterile liquid, such as oil, water, ethanol and theircombination may be used for preparing the pharmaceutical preparations inthe form of liquid suspension or solution.

For oral or parenteral drug delivery, pharmacy-suitable surfactant,suspending agent or emulsifier may be added. Suspension may contain oil,such as peanut oil, sesame oil, cottonseed oil, corn oil, and olive oil.Suspension preparation may also contain fatty acid ester, such as oleicacid ethyl ester, isopropyl myristate; fatty acid glyceride and acetylfatty acid glyceride. Suspension preparations may include ethanol, suchas alcohol, isopropanol, hexadecanol, glycerol and propylene glycol;ether such as poly (ethylene glycol); petroleum hydrocarbon, such asmineral oil and vaseline, and water can also be used for suspensionpreparation.

The compositions adopt the form of pill, tablet or capsule. Therefore,the compositions may contain one or more diluents, such as lactose, canesugar, dicalcium phosphate, etc; disintegrants, such as starch or theirderivatives; lubricants, such as magnesium stearate, etc; and/oradhesives, such as starch, Arabic gum, polyvinylpyrrolidone, gelatin,cellulose, and their derivatives. Tablet may be prepared with anypressing or molding method known to the technical personnel in thefield. Tablet may be prepared and pressed through pressing optionallythe compounds of the present invention in the form of free flow mixedwith auxiliary elements (such as adhesive, lubricant, diluent,disintegrant or dispersing agent) in suitable machine. Molding tabletmay be prepared by molding powder mixture of the compound of the presentinvention with any suitable carrier in suitable machine.

Or the medicinal compositions of the present invention may be in thesuppository form of rectal administration. Such suppositories may beprepared by mixing the drug with appropriate non-irritating excipient,which is solid under room temperature but is liquid under rectaltemperature and thus release drug in rectum. Such materials includecocoa butter, beewax, polyethylene glycol, hard fat and/or hydrogenatedcoco-glyceride. The compositions suitable for rectal administration mayalso contain rectal enema unit. Such unit contains one or more compoundsof the present invention and pharmaceutical acceptable menstruum (suchas 50% ethanol aqueous solution or salt aqueous solution). Suchmenstruum is physiologically compatible with rectum and/or colon. Rectalenema unit contains the applicator tip protected by inert cover.

This tip, preferably, is composed of polyethylene, lubricated withlubricant such as white vaseline, preferably protected by one-way valve,to prevent the backflow of the drug delivered. Rectal enema unit shallhave sufficient length, preferably 2 inches, and inserted into colon viaanus.

The medicinal compositions of the present invention may also be in theform of local drug delivery, especially when therapeutical targetincludes the region or organ locally accessible. The diseases of thoseorgans include the diseases of eye, skin or lower intestinal tract. Itis easy to prepare suitable topical preparation used for the regions ororgans in those regions or organs. In case of topical administration,the compound of the present invention containing one or more compositesmay be in the form of emulsion, lotion, gel, foam, cream, gelatin,solution, suspension, ointment and transdermal patch.

Topical administration at lower intestinal tract can be realized throughrectal suppository preparation or suitable enema preparation. Topicaltransdermal patch may be used as well. In case of topical application,the medicinal composition in appropriate ointment form may be prepared.Such ointment contains the active ingredient suspended on or dissolvedin one or more carriers. The carriers used for the topical delivery ofthe compound in the present invention include but not limited to mineraloil, liquid Vaseline, white Vaseline, propylene glycol, polyoxyethylene,polypropylene oxide compound, emulsifying wax and water. Or, themedicinal composition in appropriate lotion or cream form may beprepared. Such lotion or creation contains the active ingredientssuspended on or dissolved in one or more pharmaceutical acceptablecarriers. Suitable carriers include mineral oil, Span-60, Tween-60,cetyl, wax, cetanol, 2-octyldodecanol, benzyl alcohol and water.

The medicinal composites of the present invention may be deliveredthrough nose aerosol or suction. In case of inhalation delivery, thecomposites in the form of dry powered or liquid may be delivered throughsprayer. Such composites are prepared with the known technology inpharmaceutical preparation field. Moreover, the composites in the formof solution may be prepared in saline with benzyl alcohol or othersuitable corrosion remover, absorption enhancer for reinforcingbioavailability, fluorocarbon compound and/or other conventionalsolubilizer or dispersing agent.

The pharmaceutical acceptable carriers that can be used for thosecomposites include ion exchanger, aluminum oxide, aluminum stearate,lecithin; serum protein such as human serum albumin; buffer substancesuch as phosphate; glycine, sorbic acid, potassium sorbate, partialglyceride mixture of saturate plant fatty acid, water, salt orelectrolyte such as sulfuric acid protamine, sodium hydrogen phosphate,potassium hydrogen phosphate, sodium chloride, zinc salt; colloidalsilicon dioxide, magnesium trisilicate, polyvinylpyrrolidone, cellulosesubstance, polyethylene glycol, sodium carboxymethylcellulose,polyacrylate, wax, polyethylene-polypropylene oxide-block polymer,polyethylene glycol and wool fat.

Examples of suitable excipients include but not limited to water,saline, lactose, glucose, cane sugar, sorbitol, Mannitol, starch, Arabicgum, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate,microcrystalline cellulose, polyvinylpyrrolidone, cellulose, syrup,methylcellulose, ethyl cellulose, hydroxypropyl methyl cellulose andpolyacrylic acid, such as carbopol. The composites may include lubricantsuch as talcum powder, magnesium stearate and mineral oil; wettingagent; emulsifier; suspending agent; corrosion remover such as methyl-,ethyl- and propyl-hydroxyl-benzoate; pH modifier such as inorganic andorganic acid and alkali; sweetening agent; and corrigent.

In addition to above representative dosage forms, the technicalpersonnel in the field usually know other pharmaceutical acceptableexcipients, carriers and dosage forms, which are included in the presentinvention. It is understood that the specific dosage and therapeuticalschedule for any specific patient are decided by many factors. Theyinclude the activity of specific compound used, patient's age, weight,general health condition, gender, diet, drug administration time,discharge rate, combination, judgment of therapist and severity ofspecific disease treated. The quantity of active ingredient is alsodecided by specific compound and other therapeutic drug in (if any)composites.

The above pharmaceutical composites can further include other activeingredients for treating or auxiliary treating proliferating diseases,or the other combined use of the drugs for treating or auxiliarytreating proliferating disease, such as the combined use ofanti-proliferative agent, immunomodulator, anticancer drug, cytotoxicagent, and anticancer aided drug beyond the present invention.

Other examples of those therapeutic agents include: anti-proliferativeagent, such as methotrexate; FK506 (fujimycin, Prograf), mycophenolatemofetil; cytotoxic drugs, such as azathioprine and cyclophosphamide;TNF-α inhibitor, such as Tenidap; anti-TNF antibody or soluble TNFreceptor, such as etanercept (Enbrel); Rapamycin, Ieflunimide, andcyclo-oxygenase-2 (COX-2) inhibitor, such as celecoxib and rofecoxib, ortheir derivatives; and the PTK inhibitor that the existing technologyhas been made public.

Typical anticancer drugs and cytotoxic agents include but not limitedto: alkylating agent, such as chlormethine, alkylsulphonate, nitrourea,aziridine and triazene; antimetabolite, such as Folate antagonist,purineanalogue and pyrimidine analogue; antibiotics, such as anthracenenucleus, bleomycin, mitomycin, dactinomycin and streptomyces plicatus;enzyme, such as L-asparaginase; farnesyltransferase inhibitor; hormonedrug, such as glucocorticoid, estrogen/antiestrogen,androgen/antiandrogen, pregnendione, luteinizing hormone releasinghormone antagonist, acetic acid Sandostatin; microtubules breaker, suchas ecteinascidin or its analogue and derivant; microtubules stabilizer,such as paclitaxel, docetaxel and epothilone or their analogues orderivatives; products derived from plants, such as Vinca Alkaloids,epipodophyllotoxin, taxane; topoisomerase inhibitor; isoprene basedprotein transferase inhibitor; miscellaneous reagents, such ashydroxycarbamide, Procarbazine, Mitotane, hexamethyl melamine, platinumcoordinated complex such as cisplatin and Carboplatin; and other drugsused for anticancer and cytotoxic agent, such as biological responseregulator, growth factor; and immunomodulator and monoclonal antibody.The compound of the present invention may also be used in combinationwith radiotherapy.

The examples of anticancer drugs and cytotoxic agents in the samecategory include but not limited to: chlormethine hydrochloride,cyclophosphamide, chlorambucil, betamerphalan, ifosfamide, busulfan,carmustine, lomustine, semustine, streptozotocin, thiotepa, dacarbazine,methotrexate, sulfur guanopterin, thiol petrin, fludarabine,Pentastatin, leustatin, cytarabine, fluorouracil, doxorubicinhydrochloride, daunorubicin, idarubicin, sulfuric acid bleomycin,mitomycin C, Dactinomycin D, safracins, Micronomicin, quinocarcins,discodermolides, vincristine, vincaleukoblastinum, Corvino libintartrate, etoposide, teniposide, paclitaxel, tamoxifen, estramustine,phosphoric acid estramustine sodium salt, Flutan, Buserelin, Lupron,pteridine, diyne, levomisole, aflacon, interferon, interleukin,Aldesleukin, Felsdine, myeloid growth factor, rituximab, BCG, vitamin Aacid, irinotecan hydrochloride, betamethasone, gemcitabinehydrochloride,hexamethy and Topotecan, and any of their analogues or derivatives.

The preferred members in those categories include but not limited to:paclitaxel, cisplatin, carboplatin, adriamycin, idarubicin,daunorubicin, aminopterin, methotrexate, methyl petrin, mitomycin C,ecteinascidin, pholipomycin, 5-fluorouracil, 6-thiol petrin,gemcitabine, cytarabine, podophyllotoxin or podophyllotoxin derivant,such as etoposide, phosphoric acidetoposide or teniposide,betamerphalan, vincaleukoblastinum, vincristine, leurosidine, vindesineand leurosine.

Examples of antitumor drugs and other cytotoxic agents include: U.S.patent application Ser. No. 09/506,481, submitted on Feb. 17, 2000,German patents 41380428, WO97/19086, WO98/22461, WO98/25929, WO98/38192,WO99/01124, WO99/02224, WO99/02514, WO99/03848, WO99/07692, WO99/27890,WO99/28324, WO99/43653, WO99/54330, WO99/54318, WO99/54319, WO99/65913,WO99/67252, WO99/67253, and epothilone derivatives in WO00/00485; cellcycle protein dependent kinase inhibitor in WO99/24416; and isopreneprotein transferase inhibitor in WO97/30992 and WO98/54966.

Other therapeutic agents above may use, for example, the dosage pointedout in clinical medicine manual or the dosage determined by the generaltechnical personnel in the field when using together with the compoundof the present invention.

Finally, the present invention provides a method for treating cellproliferation diseases, including effective dosage of the compound informula A delivering to the patient with requirement.

“Cell proliferation disease” refers to the disease with thecharacteristic of abnormal cell proliferation. Proliferation diseasedoes not mean any limit on cell growth rate but only represents the lossof the normal control affecting growth and cell division. Therefore, insome embodiments, the cell of proliferation disease may have the samecell division rate as normal cell without affecting the signalrestricting such growth. Within the range of neoplasm or tumor, theneoplasm or tumor of “cell proliferation disease” is the abnormal growthof tissue. “Cancer” refers to any kind of various malignant tumorscharacterized in cell proliferation. Such tumors have the capability tointrude into surrounding tissues and/or transfer to new position ofsettlement.

In general, the cell proliferation diseases that can be treated with thecompound exposed in this paper relate to any disease characterized inabnormal cell proliferation. Those include various benign or malignant,transferred or non-transferred tumor and cancer. The method described inthis paper may be used for confronting the particular characteristics oftumor, such as tissue invasion or transitivity. Cell proliferationdiseases include various tumors, which include but not limited to:

Cancer: including bladder cancer, breast cancer, colon cancer, renalcancer, liver cancer, lung cancer, cellule lung cancer, ovarian cancer,prostate cancer, pancreatic cancer, esophageal cancer, gastric cancer,gallbladder, cervical cancer, thyroid cancer and skin cancer, squamouscell carcinoma;

Hematopoietic tumors of lymphatic system: including leukemia, leukemiaof acute lymphatic system, leukemia of acute lymphoblast, β-celllymphoma, T-cell lymphoma, Hodgkins lymphoma, non-Hodgkins lymphoma,chorionic villus lymphoma and Burketts lymphoma;

Hematopoietic tumors of myeloid lineage: including acute and chronicmyelocytic leukemia, myelodysplastic syndromes and promyelocyticleukemia;

Tumors of central and peripheral nervous system: including astrocytoma,neuroturbo chargeoma, glioma and schwannoma;

Neoplasms of mesenchymal origin: including fibrosarcoma,rhabdomyosarcoma and osteosarcoma;

Other tumors: including melanoma, xenoderma pigmentosum, aminationacanthoma, seminoma, follicular thyroid carcinoma and teratocarcinoma.

The malignant proliferation disease treated includes hematologicneoplasm. This tumor is the cell hyperplasia of hemopoietic system.

The hematologic neoplasm includes lymphocytoma, wherein abnormal celloriginates from lymphoid cell lineage cells and/or the characteristicphenotype displays lymphoid cell lineage cells. Lymphoid cell tumor maybe subdivided into B cytoma, T and NK cytoma, and Hodgkin lymphoma. Bcytoma can be further divided into ancestor B cytoma andmature/peripheral B cytoma. The illustrational B cytoma is precursor Blymphocyte leukemia/lymphoma (precursor B cell acute lymphocyteleukemia), while the illustrational mature/peripheral B cytoma is B cellchronic lymphocyte leukemia/small lymphocyte lymphoma, B cellprolymphocyte leukemia, lymphoplasmacytic lymphoma, splenic marginalregion B cell lymphoma, hairy cell leukemia, plasma cellmyeloma/plasmacytoma, MALT type universal domain area B cell lymphoma,section area B cell lymphoma, follicle lymphoma, jacket cell lymphoma,diffuse large B cell lymphoma, mediastinal large B cell lymphoma,primary effusion lymphoma and Burkittl ymphoma/Burkitt cell leukemia. Tcell and Nk cytoma can be further divided into precursor T cell cancerand mature (peripheral) T cytoma. Illustrational precursor T cytoma isprecursor T-lymphocyte lymphoma/leukemia (precursor T cell acutelymphocyte leukemia), while illustrational mature (peripheral) T cytomais T cellprolymphocyte leukemia T cell particle lymphocyte leukemia,aggressive NK cell leukemia, adult T cell lymphoma/leukemia (HTLV-1),extranodal nasal type NK/T cell lymphoma; nasal form, pathotype T celllymphoma, hepatolienal γ-6 T cell lymphoma, subcutaneous panniculitis Tcell lymphoma, granuloma fungoides/Sezary syndrome, retrogressivemaxicell lymphoma; T/invalid cell, primary skin type peripheral T celllymphoma, non-additionally characterized blood vessel immunoblasticlymphadenopathy T cell lymphoma, retrogressive maxicell lymphoma,T/invalid cell, and primary body type. The third type of lymphoid celltumor is Hodgkin lymphoma, also called as Hodgkin's disease. Theillustrative diagnosis of the disease treated with the said compoundincludes but not limited to nodular lymphocyte predominant Hodgkinlymphoma and various Hodgkin's diseases in classic form, wherein theillustrational diseases are nodual hardening Hodgkin lymphoma (Level 1and Level 2), lymphocyte-enriched classic Hodgkin lymphoma, Hodgkinlymphoma composed of mixed cells and lymphocytic depletion Hodgkinlymphoma.

The hematologic neoplasm also includes myelocytome. Such tumor includesa major category of malignant proliferation disease involving ordisplaying the cell characteristic phenotype of myelocyte spectrum.Myelocytome may be subdivided into myeloproliferative disease,myeloproliferative disorder/myelodysplastic disease, myelodysplasticsyndrome and acute myeloid leukemia. Illustrational myelodysplasticdisease includes chronic myelogenous leukemia, chronic neutrophilsleukemia, chronic eosinophilic pneumonia leukemia/hypereosinophilicsyndrome, chronic idiopathic myelofibrosis, polycythemia and primarythrombocythemia. Illustrational myeloproliferativedisorder/myelodysplastic disease includes chronic myelomonocyticleukemia, atypical chronic myelogenous leukemia and teenager acutemyelomonocytic leukemia. Illustrational myelodysplastic syndromeincludes the refractory anemia with and without annular sideroblast,refractory pancytopenia (myelodysplastic syndrome) with multilinkagedysplasia, refractory anemia (myelodysplastic syndrome) with excessivegerm cell, 5q-syndrome and myelodysplastic syndrome. The compound of thepresent invention can be used for treating any relevant myelocytome.

The above compounds can be used for treating acute myeloid leukemia(AML). Such leukemia represents a major category of myelocytome in whichthe diseases may be further divided. Such branches include but notlimited to AML with recurrent chromosomal translocation, AML withmultilinkage dysplasia and other unclassified AMLs. The illustrationalAMLs with recurrent chromosomal translocation include but not limited toAML with t (8; 21) (q22; q22), AML1 (CBF-α)/ETO, acute promyelocyticleukemia (AML with t(15; 17) (q22; q11-12) and variants, PML/RAR-α), AMLwith abnormal eosinophil cell (inv(16) (p13q22) or t(16; 16) (p13; q11),CBFb/MYH11X) and 11q23(MLL) abnormal AML. Other acute myeloid leukemianot classified into the category of any definition includes minimallydifferentiated AML, immature AML, mature AML, acute myelomonocyticleukemia, acute mononuclear leukemia, acute red cell leukemia, acutemegakaryocyte leukemia, acute basophil cell leukemia and acute totalleukemia with myelofibrosis.

Preferably, the treated tumors are breast cancer, lung cancer, coloncancer, gastric cancer, esophagus cancer, ovarian cancer, osteosarcoma,cervical cancer, liver cancer, cerebroma, prostate cancer, and melanoma.

The term “treatment” in the present invention indicates the relief ofthe symptom relating to symptom or disease or termination of the furtherdevelopment or deterioration of those symptoms, or stopping orpreventing disease or symptom.

The term “pharmaceutical effective dose”, “effective dose of treatment”or “therapeutically effective dose” refers to the amount of the subjectcompound that research personnel, veterinarians, physicians or otherclinical technicians are seeking the biological or medical reaction totissue, system, animal or human.

The term “effective dose of treatment” includes the dose of compounddelivered sufficient to stop the development of one or more symptoms ofdiseases or symptoms under treatment or to relieve to a certain degree.The effective dose of treatment should be changed with the compound,symptom or status and severity as well as the age, weight, etc. of themammal treated.

The term “patient” defined in this paper includes animals, such asmammal. Mammal includes but not limited to primate (such as human), cow,sheep, goat, horse, dog, cat, rabbit, rat, mice, etc. In preferredembodiment, the patient is human. The effective dose of the compound ofthe present invention may be decided by the general technical personnelin this field. For adult, the dosage is approximately 0.001 mg to 1000mg of active compound per kg of weight per day. The drug may beadministered in single dose or in respective divided dose, such as 1 to4 times per day. It should be clear that, for any specific object, thespecific dose level and administration frequency are variable anddecided by many factors, including the activity of the specific compoundused, metabolic stability and acting duration of the compound, speciesof administration object, age, weight, health status, sex, and dietaryhabit, way and time of administration, discharging rate, combination ofdrugs, and the severity of specific symptom.

Comparing with the antitumor platinum compound of the prior art, thesolubility of the ionized compound of the present invention is obviouslyimproved. The solubility of the compounds in the invention is above 80mg/ml in water. Especially for the compounds in embodiments of thepresent invention, the solubility is generally more than 100 mg/ml.Moreover, the platinum compound of the prior art cannot be salinized.The compound of this present invention can produce salt form and is morefavorable for producing into the form of stable preparation.

The above dosage forms of any compound containing effective dose arewithin the range of the conventional test and the present invention.Therapeutically effective dose may be adjusted according to theadministration route and dosage form. The representative compound of thepresent invention is the preparation showing high therapeutic index.Therapeutic index is the dose ratio between toxicity and curative effectand can be expressed by the ratio between LD₅₀ and in vivo antitumoractivity (ED₅₀) or in vitro cytotoxicity (IC₅₀). LD₅₀ is the lethal dosefor 50% population; ED₅₀ is the therapeutically effective dose for 50%population. LD₅₀ and ED₅₀ are determined in animal cell culture mediumor experimental animal through standard pharmaceutical method. SinceLD₅₀ (lethal dose for 50% animal, mg/kg) representing toxicity of thecompound in the present invention is much higher than the platinumcompound cisplatin and carboplatin, etc. of the existing technology andthe effective dose of in vivo antitumor activity and in vitroconcentration of inhibiting cell toxicity IC₅₀ value are equivalent orlower than carboplatin, it can be used for treating the patient whocannot tolerate the existing platinum compounds such as carboplatin,cisplatin, etc. and achieve better technical effect. The compound of thepresent invention may be individually used or used in combination,and/or in combined use with other suitable therapeutic agents used fortreating proliferating diseases.

Specific Implementation Modalities

The following embodiments and test examples were described in thepresent invention in details, but will not restrict the enablement ofthe present invention in any way. The technical personnel in this fieldshould understand that any modification or substitution of appropriatetechnical characteristics according to the instructions of the existingtechnology remain within the range of protection claimed by the presentinvention. The purity of the raw materials used in the present inventionis just above chemical purity. The said raw materials may be purchasedfrom market. The compounds obtained in the following embodiments are inthe form of salt. Ionized compounds may be obtained by adding alkali toregulate pH value of those compounds in the form of salt. The saidcompounds can be easily converted into other types of organic orinorganic salts by using the method of adding appropriate acid, whichpossibly include but not limited to nitrate, carbonate, bicarbonate,phosphate, hydrophosphate, dihydric phosphate, sulphate, bisulfate,phosphite, acetate, propionate, isobutyrate, malonate, benzoate,succinate, suberate, fumarate, mandelate, phthalate, benzene sulfonate,tosilate, citrate, tartrate, mesylate, arginine salt, glucuronate orgalactose acid salt, etc. This will not be explained again in thefollowing embodiments one by one.

EMBODIMENT 1 2-(4-diethylamino butyl)-malonato.Cis-diamine platinum (II)acetate Step 1: 2-(4-bromobutyl)-diethyl malonate

Diethyl malonate (16.06 g, 0.1 mol) and 1,4-dibromobutane[21.6 g, 0.1mol] were placed into 150 ml flasks. K₂CO₃ (15.12 g, 0.11 mol) andtetrabutylammonium bromide (156 mg) were added. The mixture was stirredand heated to 65˜85° C. in oil bath for 16˜24 h; suction filtration wasconducted to remove solid which was washed with diethyl ether (30 ml×3times), filtrate was consolidated; and washed with water (40 ml×3 times)then dried with MgSO₄ for 4˜8 h; After removal of solvent, thedistillate was collected for 140° C.-151° C. at vacuum 7 mmHg; Theproduct was 9.35 g; and the yield was 31.69%.

Step 2: 2-(4-diethyl amino-buty)-diethyl malonate

To the mixture of 4-bromobutyl-diethyl malonate (117.9 g, 0.4 mol),anhydrous K₂CO₃ (55.5 g, 0.4 mol) in acetonitrile (500 ml), diethylamine(73.2 g, 1.0 mol) solution in refrigerated was added and the mixture washeated at 45˜60° C. for 2-6 h; insoluble substance was filtered out andthe filtrate was concentrated in vacuo; the residues was dissolved with1000 ml ethyl acetate; organic phase was washed with saturate NaClaqueous solution (250 ml×3 times) and dried over anhydrous MgSO₄overnight; after removal of solvent in vacuo, light yellow oil (103.5 g)was obtained; the oil was purified by column chromatography to affordthe title sterling (48.55 g) and the yield was 42.29%.

Step 3: 2-(4-diethyl amino-buty)-sodium malonate

2M NaOH solution (obtained from the NaOH of 212.1 mg plus water of 2.5mL) was added to 2-(4-diethyl amino-buty)-diethyl malonate (575 mg, 2mmol) in 20 mL flasks; and the mixture was stirred at room temperaturefor 45˜60 h, 2-(4-diethyl amino-buty)-malonic acid disodium saltsolution was obtained.

Step 4: diamine.diiodo-platinum (II)

KI (6.640 g, 40 mmol) solution (50 ml) was added to potassiumchloroplatinite (K₂PtCl₄) (2.075 g, 5 mmol) in water (50 ml), themixture was stirred and heated to 40˜60° C. away from light and oxygenfor 0.5˜2 h, N2 protection, and then ammonia water (50 ml) (containing 5mmol ammonia) was added; The reaction mixture was kept under thiscondition for 0.5˜2 h. Light yellow solid product (2.29 g) was obtainedby suction filtration and washed successively with water (10 ml×3 times)and diethyl ether (10 ml×3 times); the yield was 95.1%.

Elemental analysis: H1.24% (theoretical 1.21%), N5.56% (theoretical5.797%).

Step 5: Diamine.dihydrate platinum (II) sulphate

Stirring Ag₂SO₄ (625 mg, 2 mmol) in water (30 ml) which is placed in theboiling flask-3-neck of 100 ml, diamine.diiodo-platinum (II) (0.96 g, 2mmol) was added and another part of water (40 ml) was added to thereaction mixture; the mixture was stirred and heated at 40˜60° C. for4˜8 h under the condition for N₂ protection and keeping in dark space.After removing AgI deposit by suction, the filtrate was the aqueoussolution of the product.

Step 6: 2-(4-diethylamino butyl)-malonato.Cis-diamine platinum (II)acetate

[2-(4-diethylamino butyl)-malonato disodium salt solution was regulatedthe pH to 5˜7 with HAC (1M) and then cis-diamine.dihydrate platinum (II)sulphate aqueous solution was poured into reaction mixture; the mixturewas heated in water bath to 40˜75° C. for 4-6 h under the condition forN2 protection, reaction mixture was concentrated to a certain volume andshould be at a standstill, crystalline-type product (130 mg) isobtained.

Embodiment 1 compound is soluble in water. The solubility is more than300 mg/ml. It can be easily converted into other types of organic orinorganic salts through free base. It may be but not limited tosulphate, mesylate, tartrate, succinate acetate, citrate, tosilate,fumarate, etc.

Free base elemental analysis: C28.72% (theoretical 28.82%), H5.61%(theoretical 5.46%), N8.98% (theoretical 9.17%).

¹HNMR (D₂O) (ppm): δ3.52 (m, 1H), δ2.79-2.67 (b, 4H), δ2.57-2.67 (b,2H), δ1.80 (m, 2H), δ1.45 (m, 2H), δ1.24 (m, 2H), δ1.05 (t, 6H).

EMBODIMENT 2 2-(4-diethylamino butyl)-malonato.Cis-(1,2-ethylenediamine)platinum (II) tosilate Step 1, 2 and 3: Same as [Embodiment 1] Step 1,2, and 3 Step 4: 1,2-ethanediamine.diiodo-platinum (II)

KI (6.64 g, 40 mmol) solution (40 ml) was added to potassiumchloroplatinite (K₂PtCl₄) (2.076 g, 5 mmol) in water (50 ml), themixture was stirred and heated to 40˜60° C. away from light and oxygenfor 0.5˜2 h, and then 1,2-ethylenediamine (301 mg, 5 mmol) (saled)refrigerated in water (50 ml) was added; The reaction mixture shall bekept under this condition for 0.5˜2 h. Yellow solid product (2.254 g)was obtained by suction filtration and washing successively with water(10 ml×3 times) and diethyl ether (10 ml×3 times), the yield was 89.8%.

Elemental analysis: C4.77% (theoretical 4.72%), H1.41% (theoretical1.57%), N5.41% (theoretical 5.50%).

Step 5: 1,2-ethylenediamine.dihydrate platinum (II) sulphate

Stirring Ag₂SO₄ (625 mg, 2 mmol) in water (30 ml) which is placed in theboiling flask-3-neck of 100 ml, 1 &2-ethylenediamine.diiodo-platinum(II) (1.020 g, 2 mmol) was added and another part of water (40 ml) wasadded to the reaction mixture, the mixture was stirred and heated at40˜60° C. for 4˜8 h. After removing AgI deposit by suction, the filtratewas the aqueous solution of the product. Step 6: 2-(4-diethylaminobutyl)-malonato.Cis-(1,2-ethylenediamine) platinum (II) tosilate

2-(4-diethylamino butyl)malonate disodium salt solution was regulated tothe pH 5˜7 with p-toluenesulfonic acid (C₇H₈O₃S, 1M) and then aqueous1,2-ethylenediamine.dihydrate platinum (II) sulphate was poured intoreaction mixture; the mixture was heated in water bath to 40˜60° C. for4-8 h under the condition for N₂ protection and keeping in dark space.And then added 2.5 g silica (200-300 rounds) into it, the mixture wasstirred for 15 min and concentrated to dry, the residue was purified bycolumn chromatography to afford the title compound (138 mg).

Both the free base and salt of the said compound are soluble in water inembodiment 2. The solubility is more than 300 mg/ml. It can be easilyconverted into other types of organic or inorganic salts throughionization. It may be but not limited to sulphate, mesylate, tartrate,succinate, acetate, citrate, tosilate, fumarate, etc.

Free base elemental analysis: C32.31% (theoretical 32.23%), H5.65%(theoretical 5.58%), N8.82% (theoretical 8.68%).

¹HNMR (D₂O) (ppm): δ3.51 (m, 1H), δ2.77-2.67 (br, 4H), δ2.65-2.57 (br,2H), δ2.25 (br, 4H), δ1.79 (m, 2H), δ1.44 (m, 2H), δ1.23 (m, 2H), δ1.05(t, 6H).

EMBODIMENT 3 2-(4-diethylaminobutyl)-malonato.Cis-(1,2-trans-cyclohexanediamine) platinum (II)tosilate Step 1, 2 and 3: Same as [Embodiment 1] Step 1, 2 and 3 Step 4:Trans-cyclohexanediamine.diiodo-platinum(II)

KI (6.640 g, 40 mmol) solution (40 ml) was added to potassiumchloroplatinite (K₂PtCl₄) (2.075 g, 5 mmol) in water (50 ml), themixture was stirred and heated to 40˜60° C. away from light and oxygenfor 0.5˜2 h, and then trans-cyclohexanediamine (571 mg, 5 mmol) in water(50 ml) was added; the reaction mixture shall be kept under thiscondition for 0.5˜2 h. Yellow solid product (2.709 g) was obtained bysuction filtration and washing successively with water (10 ml×3 times)and diethyl ether (10 ml×3 times), the yield was 96.2%.

Step 5: Trans-1,2 cyclohexanediamine.dihydrate platinum (II) sulfate

Stirring Ag₂SO₄ (625 mg, 2 mmol) in water (30 ml) which is placed in theboiling flask-3-neck of 100 ml, trans-cyclohexanediamine.diiodo-platinum(II) (1.126 g, 2 mmol) was added and another part of water (40 ml) wasadded to the reaction mixture; The mixture was stirred and heated at40˜60° C. for 4˜8 h under the condition for N₂ protection and keeping indark space. After removing AgI deposit by suction, the filtrate was theaqueous solution of the product.

Step 6: 2-(4-diethylaminobutyl)-malonato.Cis-(1,2-trans-cyclohexanediamine) platinum (II)tosilate

2-(4-diethylamino butyl)malonate disodium salt solution was regulated tothe pH 5˜7 with p-toluenesulfonic acid (1M) and thentrans-cyclohexanediamine.dihydrate platinum (II) sulphate was pouredinto reaction mixture; The mixture was heated in water bath to 40˜60° C.for 4-8 h. And then added 2.5 g silica (200-300 rounds) into it; themixture was stirred for 15 min and concentrated to dry, the residue waspurified by column chromatography to afford the title compound (157 mg).

Embodiment 3 compound is soluble in water. The solubility is more than300 mg/ml. It can be easily converted into other types of organic orinorganic salts through free base. It may be but not limited tosulphate, mesylate, tartrate, succinateacetate, citrate, tosilate,fumarate, etc.

Free base elemental analysis: C37.76% (theoretical 37.92%), H6.25%(theoretical 6.13%), N7.70% (theoretical 7.81%).

¹HNMR (D₂O) (ppm): δ3.52 (m, 1H), δ2.78-2.65 (br, 4H), δ2.67-2.56 (br,2H), δ2.05 (br, 2H), δ1.80 (m, 4H), δ1.46 (m, 4H), δ1.25 (m, 4H), δ1.05(t, 6H), δ1.01 (m, 2H).

EMBODIMENT 4 2-(4-(1-piperidyl)-butyl)-malonato.Cis-diamine platinum(II) phosphate Step 1: Same as [Embodiment 1] Step 1 Step 2:2-(4-(1-piperidyl)-butyl)-diethyl malonate

To the mixture of 4-brombutyl-diethyl malonate (117.7 g, 0.4 mol),anhydrous K₂CO₃ (55.6 g, 0.4 mol) in acetonitrile (500 ml), piperidine(85.0 g, 1.0 mol) solution was added and the mixture was heated at40˜60° C. for 2-6 h; insoluble substance was filtered out and thefiltrate was concentrated in vacuo; the residues was dissolved with 1000ml ethyl acetate; organic phase was washed with saturate NaCl aqueoussolution (250 ml×3 times) and dried over anhydrous MgSO4 overnight;after removal of solvent in vacuo, light yellow oil (101.2 g) wasobtained; the oil was purified by column chromatography to afford thetitle compound (36.71 g) and the yield was 30.69%.

Step 3: 2-(4-(1-piperidyl)-butyl)-diethyl malonate disodium salt

2M NaOH solution (obtained from the NaOH of 212.3 mg plus water of 2.5mL) was added to 2-(4-(1-piperidy)-butyl)-diethyl malonate (599 mg, 2mmol) in 20 mL flasks; and the mixture was stirred at room temperaturefor 45˜60 h, 2-(4-(1-piperidy)-butyl)-diethyl malonate disodium saltsolution was obtained.

Step 4, 5: Same as [Embodiment 1] Step 4, 5

Step 6: 2-(4-(1-piperidyl)-butyl)-malonato-diammine platinum (II)phosphate;

2-(4-(1-piperidyl)-butyl)-malonate disodium salt (2 mmol) solution wasregulated to the pH 5˜7 with H₃PO₄ (1M) and then aqueouscis-diamine.dihydrate platinum (II) sulphate was poured into reactionmixture; the mixture was heated in water bath to 40˜75° C. for 4-6 hunder the condition for N₂ protection, the mixture was concentrated tocertain volume and the residue was standstill at room temperature; Thecrystal type product (138 mg) was obtained.

Embodiment 4 compound is soluble in water the solubility is more than300 mg/ml. It can be easily converted into other types of organic orinorganic salts through free base. It may be but not limited tosulphate, mesylate, tartrate, succinateacetate, citrate, tosilate,fumarate, etc. Free base elemental analysis: C30.47% (theoretical30.64%), H5.13% (theoretical 5.32%), N9.00% (theoretical 8.94%).

¹HNMR (D₂O) (ppm): δ3.61 (t, 1H), δ2.83 (t, 4H), δ2.71 (t, 2H), δ1.84(m, 2H), δ1.76 (m, 4H), δ1.54 (m, 2H), δ1.42 (m, 2H), δ1.33 (m, 2H).

EMBODIMENT 5 2-(4-(1-tetrahydropyrrolo)-butyl)-malonato.Cis-diamineplatinum(II) phosphate Step 1: Same as [Embodiment 1] Step 1

Step 2: 2-(4-(1-tetralinpyrrolidyl)-butyl)-diethyl malonate

To the mixture of 4-brombutyl-diethyl malonate (118.1 g, 0.4 mol),anhydrous K₂CO₃ (55.53 g, 0.4 mol) in acetonitrile (500 ml), pyrrolidinesolution (71.2 g, 1.0 mol) was added into mixture which was then heatedat 40˜60° C. for 2-6 h; insoluble substance was filtered out and thefiltrate was concentrated in vacuo; the residues was dissolved with 1000ml ethyl acetate; organic phase was washed with saturate NaCl aqueoussolution (250 ml×3 times) and dried over anhydrous MgSO4 overnight;after removal of solvent in vacuo, light yellow oil (96.4 g) wasobtained; the oil was purified by column chromatography to afford thetitle sterling (31.23 g) and the yield was 27.39%.

Step 3: 2-(4-(1-tetralinpyrrolidyl)-butyl)-diethyl malonate disodiumsalt

2M NaOH solution (obtained from the NaOH of 213 mg plus water of 2.5 mL)was added to (1-tetralinpyrrolidyl)-butyl)-diethyl malonate (545 mg, 2mmol) in 20 mL flasks; and the mixture was stirred at room temperaturefor 45˜60 h, 2-(4-(1-tetralinpyrrolidyl)-butyl)-malonate disodium saltsolution was obtained.

Step 4, 5: Same as [Embodiment 1] Step 4, 5 Step 6:2-(4-(1-tetralinpyrrolidyl)-butyl)-malonato.cis-platinum diamine (II)phosphate

2-(4-(1-tetralinpyrrolidyl)-butyl)-malonate disodium salt solution wasregulated to the pH 5˜7 with H₃PO₄ (1M) and then cis-diamine.dihydrateplatinum (II) sulphate was poured into reaction mixture; the mixture washeated in water bath to 40˜75° C. for 4-6 h under the condition for N2protection, the mixture was concentrated to certain volume and theresidue was standstill, the crystal type product (128 mg) was obtainedby suction.

Embodiment 5 compound is soluble in water. The solubility is more than300 mg/ml. It can be easily converted into other types of organic orinorganic salts through free base. It may be but not limited tosulphate, mesylate, tartrate, succinateacetate, citrate, tosilate,fumarate, etc. Free base elemental analysis: C28.71% (theoretical28.95%), H4.97% (theoretical 5.04%), N9.37% (theoretical 9.21%).

¹HNMR (D₂O) (ppm): δ3.62 (t, 1H), δ2.83 (t, 4H), δ2.72 (t, 2H), δ1.85(m, 2H), δ1.78 (m, 4H), δ1.51 (m, 2H), δ1.33 (m, 2H).

EMBODIMENT 6 2-(3-dimethylaminocyclobutyl)-malonato.cis-diamine platinum(II) mesylate Step 1: 2-(3-bromocyclobutyl)-diethyl malonate

Diethyl malonate (16.02 g, 0.1 mol) and 1,3-dibromocyclobutyl (21.5 g,0.1 mol) were placed into 150 ml flasks. K₂CO₃ (15.13 g, 0.11 mol) andtetrabutylammonium bromide (154 mg) were added. The mixture was stirredand heated to 65˜85° C. in oil bath for 16˜24 h; suction filtration wasconducted to remove solid which was washed with diethyl ether (30 ml×3times), filtrate consolidated was washed with water (40 ml×3 times) anddried over anhydrous MgSO₄ for 4˜8 h. After removal of solvent, thedistillate was collected for 141° C.-150° C. at vacuum 7 mmHg; Theproduct was 9.21 g; and the yield was 31.43%.

Step 2: 2-(3-dimethylaminocyclobutyl)-diethyl malonate

To the mixture of 3-bromocyclobutyl-diethyl malonate (117.21 g, 0.4mol), anhydrous K₂CO₃ (55.820 g, 0.4 mol) in acetonitrile (500 ml),dimethylamine (45.2 g, 1.0 mol) solution in refrigerated was added andthe mixture was heated at 40˜60° C. for 2-6 h; insoluble substance wasfiltered out and the filtrate was concentrated in vacuo; the residue wasdissolved with 1000 ml ethyl acetate; organic phase was washed withsaturate NaCl aqueous solution (250 ml×3 times) and dried over anhydrousMgSO4 overnight; after removal of solvent in vacuo, light yellow oil(90.5 g) was obtained; the oil was purified by column chromatography toafford the title compound (41.3 g) and the yield was 40.18%.

Step 3: 2-(3-dimethylaminocyclobutyl)malonate disodium salt

2M NaOH solution (obtained from the NaOH of 213 mg or 5 mmol plus waterof 2.5 mL) was added to 2-(3-dimethylaminocyclobutyl)-diethylmalonate(514 mg, 2 mmol) in 20 mL flasks; and the mixture was stirred at roomtemperature for 45˜60 h, 2-(3-dimethylaminocyclobutyl)malonate disodiumsalt solution was obtained.

Step 4, 5: Same as [Embodiment 1] Step 4, 5 Step 6:2-(3-dimethylaminocyclobutyl)-malonato.cis-diamine platinum (II)mesylate

2-(3-dimethylaminocyclobutyl)malonate disodium salt (2 mmol) solutionwas regulated to the pH 5˜7 with methylsulfonic acid (1M) and thencis-diamine.dihydrate platinum (II) sulphate aqueous solution was pouredinto reaction mixture; the mixture was heated in water bath to 40˜75° C.for 4-6 h under the condition for N₂ protection; After filtration, thefiltrate was concentrated to a certain volume and should be at astandstill; 2-(3-dimethylaminocyclobutyl)-malonate.cis-diamine platinum(II) phosphate (143 mg) was obtained.

Embodiment 6 compound is soluble in water. The solubility is more than300 mg/ml. Free base of the compound2-(3-dimethylaminocyclobutyl)-malonic acid.cis-diamine platinum (II)could be obtained by regulating pH with alkali.

Free base elemental analysis: C25.09% (theoretical 25.23%), H4.56%(theoretical 4.44%), N9.77% (theoretical 9.81%).

¹HNMR (D₂O) (ppm): δ3.61 (d, 1H), δ2.87 (s, 6H), δ2.63 (m, 1H), δ1.73(dd, 4H), δ1.45 (m, 1H).

EMBODIMENT 7 2-(4-di-n-propylamino butyl)-malonato.cis-diammine platinum(II) phosphate Step 1: Same as [Embodiment 1] Step 1 Step 2:2-(4-di-n-propylamino butyl)-diethyl malonate

To the mixture of 4-brombutyl-diethyl malonate (118 g, 0.4 mol),anhydrous K₂CO₃ (55.2 g, 0.4 mol) in acetonitrile (500 ml),di-n-propylamine (101.2 g, 1.0 mol) solution in refrigerated was addedand the mixture was heated at 45˜60° C. for 2-6 h; insoluble substancewas filtered out and the filtrate was concentrated in vacuo; the residuewas dissolved with 1000 ml ethyl acetate; organic phase was washed withsaturate NaCl aqueous solution (250 ml×3 times) and dried over anhydrousMgSO4 overnight; after removal of solvent in vacuo, light yellow oil(117.5 g) was obtained; the oil was purified by column chromatography toafford the sterling (49.51 g) and the yield was 39.29%.

Step 3: 2-(4-di-n-propylamino butyl)-malonate disodium salt

2M NaOH solution (obtained from the NaOH of 213 mg or 5 mmol plus waterof 2.5 mL) was added to 4-di-n-propylamino butyl)-Diethyl malonate (630mg or 2 mmol) in 20 mL flasks; and the mixture was stirred at roomtemperature for 45˜60 h, 2-(4-di-n-propylamino butyl)-malonate disodiumsalt solution was obtained.

Step 4, 5: Same as [Embodiment 1] Step 4, 5 Step 6:2-(4-di-n-propylaminebutyl)-malonato.cis-diammine platinum (II)phosphate

2-(4-di-n-propylaminebutyl)-malonate disodium salt solution wasregulated to the pH 5˜7 with H₃PO₄ (1M) and then cis-diamine.dihydrateplatinum (II) sulphate aqueous solution was poured into reactionmixture; the mixture was heated in water bath to 40˜75° C. for 4-6 hunder the condition for N2 protection, after filtration, the filtratewas concentrated to a certain volume and should be at a standstill; Thecrystal type product (133 mg) was obtained.

Embodiment 7 compound is soluble in water. The solubility is more than300 mg/ml. It can be easily converted into other types of organic orinorganic salts through free base. It may be but not limited tosulphate, mesylate, tartrate, succinateacetate, citrate, tosilate,fumarate, etc.

Free base elemental analysis: C32.29% (theoretical 32.10%)); H5.72%(theoretical 6.09%); N8.59% (theoretical 8.64%).

¹HNMR (D₂O) (ppm): δ3.60 (t, 1H), δ2.77 (t, 4H), δ2.70 (t, 2H), δ1.78(m, 2H), δ1.44 (m, 2H), δ1.31 (m, 2H), δ1.25 (m, 4H), δ1.05 (t, 6H).

EMBODIMENT 8 2-(3-methyl-4-diethylamino butyl)-malonato.Cis-diamineplatinum (II) acetate Step 1: 2-(3-methyl-4-brombutyl)-diethyl malonate

Diethyl malonate (16.1 g, 0.1 mol) and 2-methyl-1,4-dibromobutane (23.0g, 0.1 mol) were placed into 150 ml flasks. K₂CO₃ (15.3 g, 0.11 mol) andtetrabutylammonium bromide (155 mg) were added. The mixture was stirredand heated to 65˜85° C. in oil bath for 16˜24 h; suction filtration wasconducted to remove solid which was washed with diethyl ether (30 ml×3times), filtrate was consolidated; and washed with water (40 ml×3 times)then dried with MgSO₄ for 4˜8 h; After removal of solvent, thedistillate was collected for 145° C.-156° C. at vacuum 7 mmHg; Theproduct was 9.65 g; and the yield was 31.23%.

Step 2: 2-(3-methyl-4-diethylamino butyl)-diethyl malonate

To the mixture of 3-methyl-4-brombutyl-diethyl malonate1 (123.6 g, 0.4mol), anhydrous K₂CO₃ (55.6 g, 0.4 mol) in acetonitrile (500 ml),diethylamine (73.3 g, 1.0 mol) solution in refrigerated was added andthe mixture was heated at 45˜60° C. for 2-6 h; insoluble substance wasfiltered out and the filtrate was concentrated in vacuo; the residueswas dissolved with 1000 ml ethyl acetate; organic phase was washed withsaturate NaCl aqueous solution (250 ml×3 times) and dried over anhydrousMgSO₄ overnight; after removal of solvent in vacuo, light yellow oil(105.7 g) was obtained; the oil was purified by column chromatography toafford the title compound (49.75 g) and the yield was 41.32%.

Step 3: 2-(3-methyl-4-diethylamino butyl)malonate disodium salt

2M NaOH solution (obtained from the NaOH of 212.1 mg or 5 mmol pluswater of 2.5 mL) was added to 2-(4-diethylamino butyl)-diethyl malonate(602 mg, 2 mmol) in 20 mL flasks; and the mixture was stirred for 45˜60h at room temperature for 2-(4-diethylamino butyl)malonate disodium saltsolution was obtained.

Step 4, 5: Same as [Embodiment 1] 4,5 Step 6: 2-(3-methyl-4-diethylaminobutyl)-malonato.cis-diamine platinum (II) acetate

2-(3-methyl-4-diethylamino butyl)malonate disodium salt solution (2mmol) was regulated to the pH 5˜7 with HAC (1M) and thencis-diamine.dihydrate platinum (II) sulphate aqueous solution was pouredinto reaction mixture; the mixture was heated in water bath to 40˜75° C.for 4-6 h under the condition for N₂ protection; After filtrationthrough celite, reaction mixture was concentrated to a certain volumeand should be at a standstill; the crystal type product (137 mg) isobtained.

Embodiment 8 compound is soluble in water. The solubility is more than300 mg/ml. It can be easily converted into other types of organic orinorganic salts through free base. It may be but not limited tosulphate, mesylate, tartrate, succinateacetate, citrate, tosilate,fumarate, etc.

Free base elemental analysis: C30.71% (theoretical 30.51%), H5.63%(theoretical 5.72%), N8.99% (theoretical 8.90%).

¹HNMR (D₂O) (ppm): δ3.52 (m, 1H), δ2.79-2.67 (b, 4H), δ2.57-2.67 (b,2H), δ1.80 (m, 1H), δ1.45 (m, 2H), δ1.25 (m, 2H), δ1.15 (d, 3H), δ1.05(t, 6H).

EMBODIMENT 92-(4-(1-piperidyl)butyl)-malonato.cis-(1,2-trans-cyclohexanediamine)platinum(II) tosilate Step 1: Same as [Embodiment 1] Step 1 Step 2, 3:Same as [Embodiment 4] Step 2, 3 Step 4, 5: Same as [Embodiment 3] Step4, 5 Step 6:2-(4-(1-piperidyl)-butyl)-malonato.cis-(1,2-trans-cyclohexanediamine)platinum (II) tosilate

2-(4-(1-piperidyl)butyl)malonate disodium salt solution was regulated tothe pH 5˜7 with p-toluenesulfonic acid (1M) and then aqueoustrans-cyclohexanediamine.dihydrate platinum (II) sulphate was pouredinto reaction mixture; the mixture was heated in water bath to 40˜60° C.for 4-8 h under the condition for N₂ protection, and then added 2.5 gsilica (200-300 rounds) into it; The mixture was stirred for 15 min andconcentrated to dry, the residue was purified by column chromatographyto afford the title compound (168 mg).

Embodiment 9 compound is soluble in water. The solubility is more than300 mg/ml. It can be easily converted into other types of organic orinorganic salts through free base. It may be but not limited tosulphate, mesylate, tartrate, succinateacetate, citrate, tosilate,fumarate, etc.

Free base elemental analysis: C39.46% (theoretical 39.27%), H6.22%(theoretical 6.0%), N7.73% (theoretical 7.64%).

¹HNMR (D₂O) (ppm): δ3.52 (m, 1H), δ2.78-2.65 (br, 4H), δ2.67-2.56 (br,2H), δ2.51 (m, 2H), δ2.02 (m, 4H), δ1.86 (m, 2H), δ1.75 (m, 4H), δ1.45(m, 2H), δ1.32 (m, 2H), δ1.21 (m, 4H), δ1.11 (t, 2H).

EMBODIMENT 102-(4-(2-methyl-1-tetralinpyrrolidyl)butyl)-malonato.cis-diammineplatinum (II) phosphate Step 1: Same as [Embodiment 3] Step 1 Step 2:2-(4-(2-methyl-1-tetralinpyrrolidyl)-butyl)-diethyl malonate

To the mixture of 4-brombutyl-diethyl malonate (118 g, 0.4 mol),anhydrous K₂CO₃ (55.6 g, 0.4 mol) in acetonitrile (500 ml), 2-methylMethylpyrrolidine solution (85.1 g, 1.0 mol) was added into reactingsolution (2-methyl Methylpyrrolidine may despun, is R type or S-type)which was then heated at 40˜60° C. for 2-6 h; insoluble substance isfiltered out and the filtrate was concentrated in vacuo; the residueswas dissolved with 1000 ml ethyl acetate; organic phase was washed withsaturate NaCl aqueous solution (250 ml×3 times) and dried over anhydrousMgSO4 overnight; after removal of solvent in vacuo, light yellow redtransparent (110.5 g) was obtained; the oil was purified by columnchromatography to afford the title sterling (39.1 g) and the yield was32.69%.

Step 3: 2-(4-(2-methyl-1-tetralinpyrrolidyl)-butyl)-diethylmalonatedisodium salt

2M NaOH solution (obtained from the NaOH of 212.3 mg or 5 mmol pluswater of 2.5 mL) was added to2-(4-(2-methyl-1-tetralinpyrrolidyl)-butyl)-diethyl malonate (598 mg, 2mmol) in 20 mL flasks; and the mixture was stirred at room temperaturefor 2-(4-(2-methyl-1-tetralinpyrrolidyl)-butyl)malonate disodium saltsolution was obtained.

Step 4, 5: Same as [Embodiment 1] Step 4, 5 Step 6:2-(4-(2methyl-1-tetralinpyrrolidyl)-butyl)-malonato.cis-diammineplatinum (II) phosphate

2-(4-(2-methyl-1-tetralinpyrrolidyl)-butyl)malonate disodium saltsolution was regulated to the pH 5˜7 with H₃PO₄ (1M) and then aqueouscis-diamine.dihydrate platinum (II) sulphate was poured into reactionmixture; the mixture was heated in water bath to 40˜75° C. for 4-6 hunder the condition for N₂ protection, the mixture was concentrated tocertain volume and the residue was standstill; The crystal type product128 mg was obtained by suction (Mseo-form, R-type or S-type).

Embodiment 10 compound is soluble in water. The solubility is more than300 mg/ml. It can be easily converted into other types of organic orinorganic salts through free base. It may be but not limited tosulphate, mesylate, tartrate, succinateacetate, citrate, tosilate,fumarate, etc.

Free base elemental analysis: C35.62% (theoretical 35.47%), H6.26%(theoretical 6.16%), N10.39% (theoretical 10.34%).

¹HNMR (D₂O) (ppm): δ3.61 (t, 1H), δ2.85 (t, 2H), δ2.72 (m, 1H), δ2.61(t, 2H), δ1.84 (m, 2H), δ1.78 (m, 2H), δ1.67 (m, 2H), δ1.45 (m, 2H),δ1.27 (d, 3H), δ1.12 (m, 2H).

EMBODIMENT 112-(4-amidobutyl)-malonato.cis-(1,2-trans-cyclohexanediamine) platinum(II) phosphate Step 1: Same as [Embodiment 1] Step 1 Step 2:2-(4-amidobutyl)-diethyl malonate

To the mixture of 2-brombutyl-diethyl malonate (118 g, 0.4 mol),anhydrous K₂CO₃ (55 g, 0.4 mol) in acetonitrile (500 ml), throughputammonia was added into mixture which was then heated at 40˜50° C. for2-6 h; insoluble substance is filtered out and the filtrate wasconcentrated in vacuo; the residues was dissolved with 1000 ml ethylacetate; organic phase was washed with saturate NaCl aqueous solution(250 ml×3 times) and dried over anhydrous MgSO₄ overnight; after removalof solvent in vacuo, light yellow oil (80.5 g) was obtained; the oil waspurified by column chromatography to afford the title compound (36.5 g)and the yield was 39.5%.

Step 3: 2-(4-amidobutyl)malonate disodium salt

2M NaOH solution (obtained from the NaOH of 215 mg or 5 mmol plus waterof 2.5 mL) was added to 2-(4-amidobutyl)-diethyl malonate (462 mg, 2mmol) in 20 mL flasks; and the mixture was stirred at room temperaturefor 45˜60 h, 2-(4-amidobutyl)malonate disodium salt solution wasobtained.

Step 4, 5: Same as [Embodiment 3] Step 4, 5 Step 6:2-(4-amidobutyl)-malonato.cis-(1,2-trans-cyclohexanediamine) platinum(II) phosphate

2-(4-amidobutyl)malonate disodium salt solution was regulated to the pH5˜7 with H₃PO₄ (1M) and then trans-cyclohexanediamine.dihydrate platinum(II) sulphate solution was poured into reaction mixture; the mixture washeated in water bath to 40˜60° C. for 4-8 h under the condition for N₂protection, and then added 2.5 g column chromatography silica gel(200-300 rounds) into it; The mixture was stirred for 15 min andconcentrated to dry, the residue was purified by column chromatographyto afford the title compound (151 mg).

Embodiment 11 compound is soluble in water. The solubility is more than300 mg/ml. It can be easily converted into other types of organic orinorganic salts through free base. It may be but not limited tosulphate, mesylate, tartrate, succinateacetate, citrate, tosilate,fumarate, etc.

Free base elemental analysis: C32.32% (theoretical 32.37%), H4.95%(theoretical 5.19%), N8.97% (theoretical 8.71%).

¹HNMR (D₂O) (ppm): δ3.61 (t, 1H), δ2.78 (t, 2H), δ2.06 (br, 2H), δ1.81(m, 2H), δ1.74 (m, 2H), δ1.46 (m, 2H), δ1.33 (m, 2H), δ1.21 (br, 2H),δ1.11 (m, 2H), δ1.01 (m, 2H).

EMBODIMENT 12 2-(4-ethylaminobutyl)-malonato.cis-(1,2-trans-cyclohexanediamine) platinum (II)phosphate Step 1: Same as [Embodiment 1] Step 1 Step 2:2-(4-ethylamidobutyl)-diethyl malonate

To the mixture of 4-brombutyl-diethyl malonate (118 g, 0.4 mol) in theboiling flask-3-neck, anhydrous K₂CO₃ (55.2 g, 0.4 mol) in acetonitrile(500 ml), ethylamine (45 g, 1.0 mol) refrigerated was added and themixture was heated at 40˜60° C. for 2-6 h; insoluble substance wasfiltered out and the filtrate was concentrated in vacuo; the residueswas dissolved with 1000 ml ethyl acetate; organic phase was washed withsaturate NaCl aqueous solution (250 ml×3 times) and dried over anhydrousMgSO₄ overnight; after removal of solvent in vacuo, light yellow oil(87.7 g) was obtained; the oil was purified by column chromatography toafford the title compound (38.6 g) and the yield was 37.26%.

Step 3: 2-(4-ethylamidobutyl)malonate disodium salt

2M NaOH solution (obtained from the NaOH of 214 mg or 5 mmol plus waterof 2.5 mL) was added to 2-(4-amidobutyl)-diethyl malonate (514 mg, 2mmol) in 20 mL flasks; and the mixture was stirred at room temperaturefor 45˜60 h, 2-(4-ethylamidobutyl)malonate disodium salt solution wasobtained.

Step 4, 5: Same as [Embodiment 3] Step 4, 5 Step 6:2-(4-ethylamidobutyl)-malonato.cis-(1,2-trans-cyclohexanediamine)platinum (II) phosphate

2-(4-ethylamidobutyl)malonate disodium salt solution was regulated tothe pH 5˜7 with H₃PO₄ (1M), and then trans-cyclohexanediamine.dihydrateplatinum (II) sulphate was poured into reaction mixture; the mixture washeated in water bath to 40˜60° C. for 4-8 h. And then added 2.5 g silica(200-300 rounds) into it; the mixture was stirred for 15 min andconcentrated to dry, the residue was purified by column chromatographyto afford the title compound (151 mg).

Embodiment 12 compound is soluble in water. The solubility is more than300 mg/ml. It can be easily converted into other types of organic orinorganic salts through free base. It may be but not limited tosulphate, mesylate, tartrate, succinateacetate, citrate, tosilate,fumarate, etc.

Free base elemental analysis: C35.55% (theoretical 35.29%), H5.71%(theoretical 5.69%), N8.46% (theoretical 8.24%).

¹HNMR (D₂O) (ppm): δ3.61 (t, 1H), δ2.77 (q, 2H), δ2.71 (m, 2H), 2.07(br, 2H), 1.81 (m, 2H), δ1.71 (m, 2H), 1.46 (m, 2H), 1.35 (m, 2H), 1.26(m, 2H), 1.17 (br, 2H), δ1.07 (t, 3H) 1.01 (m, 2H).

EMBODIMENT 132-[4-(N-methyl-N-isopropylamido)butyl]-malonato.cis-(1,2-trans-cyclohexanediamine)platinum (II) acetate Step 1: Same as [Embodiment 1] Step 1 Step 2:2-[4-(N-methyl-N-isopropylamido)butyl]-diethyl malonate

To the mixture of 4-bromethyl-diethyl malonate (118.1 g, 0.4 mol),anhydrous K₂CO₃ (55.0 g, 0.4 mol) in acetonitrile (500 ml),methylisopropylamine (73.1 g, 1.0 mol) refrigerated was added and themixture was heated at 45˜60° C. for 2-6 h; insoluble substance wasfiltered out and the filtrate was concentrated in vacuo; the residueswas dissolved with 1000 ml ethyl acetate; organic phase was washed withsaturate NaCl aqueous solution (250 ml×3 times) and dried over anhydrousMgSO₄ overnight; after removal of solvent in vacuo, light yellow oil(105.3 g) was obtained; the oil was purified by column chromatography toafford the sterling (48.54 g) and the yield was 42.28%

Step 3: 2-[4-(N-methyl-N-isopropylamido)butyl]malonate disodium salt

2M NaOH solution (obtained from the NaOH of 212 mg or 5 mmol plus waterof 2.5 mL) was added to 2-[4-(N-methyl-N-isopropylamido)butyl]-diethylmalonate (576 mg, 2 mmol) in 20 mL flasks; and the mixture was stirredat room temperature for 45˜60 h,2-([4-(N-methyl-N-isopropylamido)butyl]malonate disodium salt solutionwas obtained.

Step 4, 5: Same as [Embodiment 1] Step 4, 5 Step 6:2-[4-(N-methyl-N-isopropylamido)butyl]-malonato.cis-(1,2-trans-cyclohexanediamine)platinum (II) acetate

2-[4-(N-methyl-N-isopropylamido)butyl]malonate disodium salt solutionwas regulated to the pH 5˜7 with HAC (1M) and then aqueouscis-diamine.dihydrate platinum (II) sulphate was poured into reactionmixture; the mixture was heated in water bath to 40˜75° C. for 4-6 hunder the condition for N₂ protection, the mixture was concentrated tocertain volume and the residue was standstill; The title compound (145mg) was obtained.

Embodiment 13 compound is soluble in water. The solubility is more than300 mg/ml. It can be easily converted into other types of organic orinorganic salts through free base. It may be but not limited tosulphate, mesylate, tartrate, succinateacetate, citrate, tosilate,fumarate, etc.

Free base elemental analysis: C28.63% (theoretical 28.82%), H5.64%(theoretical 5.46%), N9.06% (theoretical 9.17%).

¹HNMR (D₂O) (ppm): δ3.51 (m, 1H), δ2.76-2.65 (b, 4H), δ2.65-2.57 (b,2H), δ1.80 (m, 2H), δ1.45 (m, 2H), δ1.24 (m, 2H), δ1.05 (d, 6H).

EMBODIMENT 14 2-(4-diethylaminobutyl)-malonato.cis-(1,2-trans-cyclopentyl diamine) platinum (II)phosphate Step 1, 2 and 3: Same as [Embodiment 1] Step 1, 2, and 3 step4: 1,2-trans-cyclopentyl diamine

To the solution of cyclopentane (6.81 g, 100 mmol) in dichloromethane(30 ml), Br₂ (16.5 g, 103 mmol) was added dropwise slowly at −5˜10° C.and stirred for 1˜3 h, organic layer was washed with saturate sodiumbicarbonate solution (10 ml×3 times) and dry with anhydrous MgSO₄ for2˜3 h; After removal of solvent in vacuo, 1,2-trans-dibromo cyclopentane(20.56 g) as light yellow transparent oil was obtained; and the yield is90.18%.

Elemental analysis: C26.51% (theoretical 26.32%), H3.62% (theoretical3.51%).

1,2-trans-dibromo cyclopentane (11.5 g, 50 mmol) and 30% ammonia ethanolsolution (30 ml) was added into 100 ml pressure reactor; the mixture washeated to 40˜60° C. and stirred for 6˜8 h; After removal of solvent invacuo to afford 1,2-trans-cyclopentylamine (4.015 g) as light yellowtransparent oil; and the yield was 79.6%.

Elemental analysis: C60.21% (theoretical 60%), H12.12% (theoretical12%), N28.21% (theoretical 28%).

Step 5: 1,2-trans-cyclopentane diamine.diiodo.platinum (II)

KI (6.63 g, 40 mmol) solution (50 ml) was added to potassiumchloroplatinite (K₂PtCl₄) (2.073 g, 5 mmol) in water (50 ml), keep indark place and the mixture was stirred and heated to 40˜60° C. away fromlight and oxygen for 0.5˜2 h, and then 1,2-trans-cyclopentane diamine(501 mg, 5 mmol) in water (50 ml) was added; The reaction mixture waskept under this condition for 0.5˜2 h. Yellow solid product was obtainedby suction filtration and washing successively with water (10 ml×3times) and diethyl ether (10 ml×3 times), the yield was 93.3%. Theproduct of 2.561 g was obtained.

Elemental analysis: C10.78% (theoretical 10.93%), H2.31% (theoretical2.19%), N4.98% (theoretical 5.10%).

Step 6: 1,2-trans-cyclopentane diamine.dihydrate platinum (II) sulphate

Stirring Ag₂SO₄ (625 mg, 2 mmol) in water (30 ml),1,2-trans-cyclopentane diamine.diiodo.platinum (II) (1.10 g, 2 mmol) wasadded and another part of water (40 ml) was added to the reactionmixture; the mixture was stirred and heated at 40˜60° C. for 4˜8 h.After removing AgI deposit by suction, the filtrate was the aqueoussolution of the product.

Step 7: 2-(4-diethylaminobutyl)-malonato.cis-(1,2-trans-cyclopentyldiamine) platinum (II)phosphate

2-(4-diethylamino butyl)malonate disodium salt solution was regulated tothe pH 5˜7 with H₃PO₄ (1M) and then aqueous 2-trans-cyclopentyldiamine.dihydrate platinum (II) sulphate was poured into reactionmixture; the mixture was heated in water bath to 40˜60° C. for 4˜8 h.And then added 2.5 g silica (200-300 rounds) into it; the mixture wasstirred for 15 min and concentrated to dry, the residue was purified bycolumn chromatography to afford the title compound (153 mg).

Embodiment 14 compound is soluble in water. the solubility is more than300 mg/ml. it can be easily converted into other types of organic orinorganic salts through free base. It may be but not limited tosulphate, mesylate, tartrate, succinateacetate, citrate, tosilate,fumarate, etc.

Free base elemental analysis: C36.57% (theoretical 36.64%), H5.73%(theoretical 5.92%), N8.17% (theoretical 8.02%).

¹HNMR (D₂O) (ppm): δ3.61 (t, 1H), δ2.77 (q, 4H), δ2.68 (t, 2H), δ2.07(br, 2H), δ1.83 (m, 2H), δ1.72 (m, 2H), δ1.48 (m, 2H), δ1.40 (m, 2H),δ1.17 (m, 2H), δ1.08 (t, 6H), δ1.02 (m, 2H).

EMBODIMENT 152-(4-diethylaminobutyl)-malonato.cis-(1,2-trans-cyclobutyldiamine)platinum (II) succinate Step 1, 2 and 3: Same as [Embodiment 1] Step 1,2 and 3 Step 4: 1,2-trans-cyclobutyldiamine

To the solution of cyclobutane (5.39 g, 100 mmol) in dichloromethane (30ml), Br₂ (16.5 g, 103 mmol) was added dropwise slowly at −5˜10° C. andstirred for 1˜3 h, organic layer was washed with saturate sodiumbicarbonate solution (10 ml×3 times) and dried with anhydrous MgSO₄ for2˜3 h; After removal of solvent in vacuo, 1,2-trans-dibromo cyclobutane(20.37 g) as light yellow transparent oil was obtained; and the yieldwas 95.19%. Elemental analysis: C22.53% (theoretical 22.43%), H2.61%(theoretical 2.80%).

1,2-trans-dibromo cyclobutane (10.65 g, 50 mmol) and 30% ammonia ethanolsolution (30 ml) was added into 100 ml pressure reactor; the mixture washeated to 40˜60° C. and stirred for 6˜8 h; After removal of solvent invacuo to afford 1,2-trans-cyclobutyldiamine (3.723 g) as light yellowtransparent oil; and the yield is 86.58%.

Elemental analysis: C55.57% (theoretical 55.81%); H11.90% (theoretical11.63%); N32.17% (theoretical 32.56%).

Step 5: 1,2-trans-cyclobutyldiamino.diiodo-platinum (II)

KI (6.63 g, 40 mmol) solution (50 ml) was added to potassiumchloroplatinite (K₂PtCl₄) (2.075 g, 5 mmol) in water (50 ml), themixture was stirred and heated to 40˜60° C. away from light and oxygenfor 0.5˜2 h, and then 1,2-trans-cyclobutyldiamine (431 mg, 5 mmol) inwater (50 ml) was added under the condition for N₂ protection andkeeping in dark space. The reaction mixture shall be kept under thiscondition for 0.5˜2 h. Yellow solid product (2.429 g) was obtained bysuction filtration and washing successively with water (10 ml×3 times)and diethyl ether (10 ml×3 times); the yield was 90.8%.

Elemental analysis: C8.75% (theoretical 8.97%), H1.91% (theoretical1.87%), N5.98% (theoretical 5.23%).

Step 6: 1,2 trans-cyclobutyldiamine.dihydrate platinum (II) sulphate

Stirring Ag₂SO₄ (627 mg, 2 mmol) in water (30 ml) which is placed in theboiling flask-3-neck of 100 ml,1,2-trans-cyclobutyldiamine.diiodo-platinum (II) (1.07 g, 2 mmol) wasadded and another part of water (40 ml) was added to the reactionmixture; the mixture was stirred, N₂ protection, kept in dark place andheated at 40˜60° C. for 4˜8 h. After removing AgI deposit by suction,the filtrate was the aqueous solution of the product.

Step 7:2-(4-diethylaminobutyl)-malonato.cis-(1,2-trans-cyclobutyldiamine)platinum (II) succinate

2-(4-diethylaminobutyl)malonate disodium salt solution was regulated tothe pH 5˜7 with succinic acid (C₄H₆O₄, 1M) and then1,2-trans-cyclobutyldiamine.dihydrate platinum (II) sulphate was pouredinto reaction mixture; the mixture was heated in water bath to 40˜60° C.for 4˜8 h with N₂ protection. And then added 2.5 g silica into it; themixture was stirred for 15 min and concentrated to dry, the residue waspurified by column chromatography to afford the product (148 mg).

Embodiment 15 compound is soluble in water. The solubility is more than300 mg/ml. It can be easily converted into other types of organic orinorganic salts through free base. It may be but not limited tosulphate, mesylate, tartrate, succinateacetate, citrate, tosilate,fumarate, etc.

Free base elemental analysis: C35.57% (theoretical 35.29%), H5.65%(theoretical 15.69%), N8.38% (theoretical 8.24%).

¹HNMR (D₂O) (ppm): δ3.61 (t, 1H), δ2.78 (q, 4H), δ2.67 (t, 2H), δ2.09(br, 2H), δ1.82 (m, 2H), δ1.72 (m, 2H), δ1.45 (m, 2H), δ1.38 (m, 2H),δ1.15 (m, 2H), δ1.06 (t, 6H).

EMBODIMENT 162-(4-diethylaminobutyl)-malonato.cis-(1,2-trans-cyclopropyl diamine)platinum (II) phosphate Step 1, 2 and 3: Same as [Embodiment 1] Step 1,2 and 3 Step 4: 1,2-trans-cyclopropyldiamine.diiodo-platinum (II)

KI (6.63 g, 40 mmol) solution was added to potassium chloroplatinite(K₂PtCl₄) (2.075 g, 5 mmol) in water (50 ml), the mixture was stirredand heated to 40˜60° C. away from light and oxygen for 0.5˜2 h., andthen 1,2-trans-cyclopropyldiamine (saled) (361 mg, 5 mmol) in water (50ml) was added; the reaction mixture was kept under this condition for0.5˜2 h. Yellow solid product (2.391 g) was obtained by suctionfiltration and washing successively with water (10 ml×3 times) anddiethyl ether (10 ml×3 times), the yield was 91.8%.

Elemental analysis: C6.97% (theoretical 6.91%), H1.41% (theoretical1.54%), N5.47% (theoretical 5.37%).

Step 5: 1,2-trans-cyclopropyldiamine.dihydrate platinum (II) sulphate

Stirring Ag₂SO₄ (624 mg, 2 mmol) in water (30 ml),2-trans-cyclopropyldiamine.diiodo-platinum (II) (1.04 g, 2 mmol) wasadded and another part of water (40 ml) was added to the reactionmixture; the mixture was stirred and heated at 40˜60° C. for 4˜8 h.After removing AgI deposit by suction, the filtrate was the aqueoussolution of the title compound.

Step 6:2-(4-diethylaminobutyl)-malonato.cis-(1,2-trans-cyclopropyldiamine)platinum (II) phosphate

2-(4-diethylaminobutyl)-malonate disodium salt solution was regulated tothe pH 5˜7 with H₃PO₄ (1M) and then aqueous1,2-trans-cyclopropyldiamine.dihydrate platinum (II) sulphate was pouredinto reaction mixture; the mixture was heated in water bath to 40˜60° C.for 4-8 h under the condition for N₂ protection and keeping in darkspace, and then added 2.5 g silica (200-300 rounds) into it; the mixturewas stirred for 15 min and concentrated to dry, the residue was purifiedby column chromatography to afford the title compound (135 mg).

Embodiment 16 compound is soluble in water. The solubility is more than300 mg/ml. It can be easily converted into other types of organic orinorganic salts through free base. It may be but not limited tosulphate, mesylate, tartrate, succinateacetate, citrate, tosilate,fumarate, etc.

Free base elemental analysis: C33.63% (theoretical 33.87%), H5.32%(theoretical 5.44%), N8.59% (theoretical 8.47%).

¹HNMR (D₂O) (ppm): δ3.62 (t, 1H), δ2.79 (q, 4H), δ2.66 (t, 2H), δ2.08(br, 2H), δ1.82 (m, 2H), δ1.45 (m, 2H), δ1.38 (m, 2H), δ1.15 (m, 2H),δ1.07 (t, 6H).

EMBODIMENT 17 2-(4-diethylaminobutyl)-malonato.cis-(1,2-ethylenediamine)platinum (II) tosilate Step 1, 2 and 3: Same as [Embodiment 1] Step 1, 2and 3 Step 4: 1,2-ethylenediamine.diiodo-platinum (II)

KI (6.64 g, 40 mmol) solution was added to potassium chloroplatinite(K₂PtCl₄) (2.076 g, 5 mmol) in water (50 ml), the mixture was stirredand heated to 40˜60° C. away from light and oxygen for 0.5˜2 h., andthen 1,2-ethylenediamine with cryopreservation (saled) (301 mg, 5 mmol)in water (50 ml) was added; the reaction mixture was kept under thiscondition for 0.5˜2 h. Yellow solid product (2.254 g) was obtained bysuction filtration and washing successively with water (10 ml×3 times)and diethyl ether (10 ml×3 times), the yield was 89.8%.

Elemental analysis: C4.77% (theoretical 4.72%), H1.41% (theoretical1.57%), N5.41% (theoretical 5.50%).

Step 5: 1,2-ethylenediamine.dihydrate platinum (II) sulphate

Stirring Ag₂SO₄ (625 mg, 2 mmol) in water (30 ml) in the boilingflask-3-neck, 1,2-ethylenediamine.diiodo-platinum(II) (1.020 g, 2 mmol)was added and another part of water (30 ml) was added to the reactionmixture; the mixture was stirred and heated at 40˜60° C. for 4˜8 h.After removing AgI deposit by suction, the filtrate was the aqueoussolution of the title compound.

Step 6: 2-(4-diethylaminobutyl)-malonato.cis-(1,2-ethylenediamine)platinum (II) tosilate

2-(4-diethylaminobutyl)-malonate disodium salt solution was regulated tothe pH 5˜7 with p-toluenesulfonic acid (C₇H₈O₃S, 1M) and then aqueous1,2-ethylenediamine.dihydrate platinum (II) sulphate was poured intoreaction mixture; N₂ protection the mixture was heated in water bath to40˜60° C. for 4-8 h, and then added 2.5 g silica (200-300 rounds) intoit, the mixture was stirred for 15 min and concentrated to dry, theresidue was purified by column chromatography to afford the titlecompound (148 mg).

Embodiment 17 compound is soluble in water. The solubility is more than300 mg/ml. It can be easily converted into other types of organic orinorganic salts through free base. It may be but not limited tosulphate, mesylate, tartrate, succinateacetate, citrate, tosilate,fumarate, etc.

Free base elemental analysis: C32.35% (theoretical 32.23%), H5.33%(theoretical 5.58%), N8.90% (theoretical 8.68%).

¹HNMR (D₂O) (ppm): δ3.63 (t, 1H), δ2.68 (q, 4H), δ2.55 (t, 2H), δ2.31(t, 4H), δ2.25 (m, 2H), δ1.86 (m, 2H), δ1.12 (m, 2H), δ1.06 (t, 6H).

EMBODIMENT 18 2-(4-diethylaminobutyl)-malonato.cis-(1,3-propane diamine)platinum (II) phosphate Step 1, 2 and 3: Same as [Embodiment 1] Step 1,2, and 3 Step 4 1,3-propane diamine.diiodo-platinum (II)

KI (6.64 g, 40 mmol) solution was added to potassium chloroplatinite(K₂PtCl₄) (2.073 g, 5 mmol) in water (50 ml), the mixture was stirredand heated to 40˜60° C. away from light and oxygen for 0.5˜2 h., andthen 1,3-propane diamine (saled) refrigerated (372 mg, 5 mmol) in water(50 ml) was added; the reaction mixture was kept under this conditionfor 0.5˜2 h. Yellow solid product (2.281 g) was obtained by suctionfiltration and washing successively with water (10 ml×3 times) anddiethyl ether (10 ml×3 times), the product is 2.281 g, the yield was87.6%.

Elemental analysis: C6.77% (theoretical 6.88%), H1.79% (theoretical1.91%), N5.43% (theoretical 5.35%).

Step 5: 1,3-propane diamine.dihydrate platinum (II) sulphate

Stirring Ag₂SO₄ (625 mg, 2 mmol) in water (30 ml) which is placed in theboiling flask-3-neck of 100 ml, 1,2-ethylenediamine.diiodo-platinum (II)1.043 g (2 mmol) was added and another part of water (40 ml) was addedto the reaction mixture; the mixture was stirred and heated at 40˜60° C.for 4˜8 h. After removing AgI deposit by suction, the filtrate was theaqueous solution of the product.

Step 6: 2-(4-diethylamino butyl)-malonato.cis-(1,3-propyl diamine)platinum (II) phosphate

2-(4-diethylamino butyl)-malonate disodium salt solution was regulatedto the pH 5˜7 with H₃PO₄ (1M) and then 1,2-ethylenediamine.dihydrateplatinum (II) sulphate was poured into reaction mixture, the mixture washeated in water bath to 40˜60° C. for 4-8 h under the condition for N₂protection and keeping in dark space, and then added 2.5 g silica(200-300 rounds) into it; The mixture was stirred for 15 min andconcentrated to dry, the residue was purified by column chromatographyto afford the product (158 mg).

Embodiment 18 compound is soluble in water. The solubility is more than300 mg/ml. It can be easily converted into other types of organic orinorganic salts through free base. It may be but not limited tosulphate, mesylate, tartrate, succinateacetate, citrate, tosilate,fumarate, etc.

Free base elemental analysis: C33.94% (theoretical 33.73%, H5.66%(theoretical 5.82%), N8.58% (theoretical 8.43%).

¹HNMR (D₂O) (ppm): δ3.61 (t, 1H), δ2.67 (q, 4H), δ2.56 (t, 2H), δ2.29(t, 4H), δ2.21 (m, 2H), δ1.82 (m, 2H), δ1.42 (m, 2H), δ1.21 (m, 2H),δ1.04 (t, 6H).

EMBODIMENT 19 2-(4-diethylaminobutyl)-malonato.cis-(1,4-butanediamine]platinum (II) phosphate Step 1, 2 and 3: Same as [Embodiment 1] Step 1,2 and 3 Step 4: 1,4-butanediamine.diiodo-platinum (II)

KI (6.635 g, 40 mmol) solution was added to potassium chloroplatinite(K₂PtCl₄) (2.071 g, 5 mmol) in water (50 ml), the mixture was stirredand heated to 40˜60° C. away from light and oxygen for 0.5˜2 h., andthen 1,4-butanediamine (saled) refrigerated (431 mg, 5 mmol) in water(50 ml) was added; the reaction mixture was kept under this conditionfor 0.5˜2 h. Yellow solid product (2.365 g) was obtained by suctionfiltration and washing successively with water (10 ml×3 times) anddiethyl ether (10 ml×3 times), the yield was 88.1%.

Elemental analysis: C8.69% (theoretical 8.94%), H2.39% (theoretical2.23%), N5.44% (theoretical 5.21%).

Step 5: 1,4-butanediamine.dihydrate platinum (II) sulphate

Stirring Ag₂SO₄ (624 mg, 2 mmol) in water (30 ml) which was placed inthe boiling flask-3-neck of 100 m, 1,2-ethylenediamine.diiodo-platinum(II) (1.072 g, 2 mmol) was added and another part of water (40 ml) wasadded to the reaction mixture, the mixture was stirred and heated at40˜60° C. for 4˜8 h. After removing AgI deposit by suction, the filtratewas the aqueous solution of the product.

Step 6: 2-(4-diethylaminobutyl)-malonato.cis-(1,4-butanediamine)platinum (II) phosphate

2-(4-diethylaminobutyl)-malonate disodium salt solution was regulated tothe pH 5˜7 with H₃PO₄ (1M) and then aqueous1,2-ethylenediamine.dihydrate platinum (II) sulphate was poured intoreaction mixture; the mixture was heated in water bath to 40˜60° C. for4-8 h under the condition for N₂ protection. And then added 2.5 g silica(200-300 rounds) into it, the mixture was stirred for 15 min andconcentrated to dry, the residue was purified by column chromatographyto afford the product (157 mg).

Embodiment 19 compound is soluble in water. The solubility is more than300 mg/ml. It can be easily converted into other types of organic orinorganic salts through free base. It may be but not limited tosulphate, mesylate, tartrate, succinateacetate, citrate, tosilate,fumarate, etc.

Free base elemental analysis: C34.95% (theoretical 35.16%), H6.02%(theoretical 6.05%), N8.13% (theoretical 8.20%).

¹HNMR (D₂O) (ppm): δ3.62 (t, 1H), δ2.66 (q, 4H), δ2.54 (t, 2H), δ2.30(t, 4H), δ2.20 (m, 2H), δ1.82 (m, 2H), δ1.41 (m, 2H), δ1.23 (m, 4H),δ1.05 (t, 6H).

EMBODIMENT 20 2-(2-diethylaminobutyl)-malonato.cis-1,2-(1,2-dihydroxymethyl)-ethyldiamine platinum (II)phosphate Step 1, 2 and 3: Same as [Embodiment 1] Step 1, 2 and 3 Step4: 1,2-(1,2-dihydroxymethyl)-ethyldiamine.diiodo-platinum (II)

KI (6.637 g, 40 mmol) solution (50 ml) was added to potassiumchloroplatinite (K₂PtCl₄) (2.073 g, 5 mmol) in water (50 ml), themixture was stirred and heated to 40˜60° C. away from light and oxygenfor 0.5˜2 h, and then 1,2-(1,2-dihydroxymethyl)ethyldiamine (601 mg, 5mmol) in water (50 ml) was added; The reaction mixture was kept underthis condition for 0.5˜2 h. Yellow solid product (2.163 g) was obtainedby suction filtration and washing successively with water (10 ml×3times) and diethyl ether (10 ml×3 times), the yield was 79.96%.

Elemental analysis: C8.65% (theoretical 8.44%), H2.39% (theoretical2.11%), N5.03% (theoretical 4.92%).

Step 5: 1,2-(1,2-dihydroxymethyl)-Ethyldiamine.dihydrate platinum (II)sulphate

Stirring Ag₂SO₄ (624 mg, 2 mmol) in water (30 ml),1,2-(1,2-dihydroxymethyl)-ethyldiamine.diiodo-platinum (II) (1.138 g, 2mmol) was added and another part of water (30 ml) was added to thereaction mixture; the mixture was stirred and heated at 40˜60° C. for4˜8 h under the condition for N₂ protection and keeping in dark space.After removing AgI deposit by suction, the filtrate was the aqueoussolution of the title compound.

Step 6:2-(4-diethylaminobutyl)-Malonato.cis-1,2-(1,2-dihydroxymethyl)-ethyldiamine]platinum (II) phosphate

2-(4-diethylaminobutyl)-malonate disodium salt solution was regulated tothe pH 5˜7 with H₃PO₄ (1M) and then aqueous1,2-(1,2-dihydroxymethyl)-ethyldiamine dihydrate platinum (II) sulphatewas poured into reaction mixture; the mixture was heated in water bathto 40˜60° C. for 4-8 h under the condition for N₂ protection. and thenadded 2.5 g silica (200-300 rounds) into it, the mixture was stirred for15 min and concentrated to dry, the residue was purified by columnchromatography to afford the title compound (138 mg).

Embodiment 20 compound is soluble in water. The solubility is more than300 mg/ml. It can be easily converted into other types of organic orinorganic salts through free base. It may be but not limited tosulphate, mesylate, tartrate, succinateacetate, citrate, tosilate,fumarate, etc.

Free base elemental analysis: C30.15% (theoretical 30.09%), H5.42%(theoretical 5.70%), N7.56% (theoretical 7.72%).

¹HNMR (D₂O) (ppm): δ3.88 (d, 4H), δ3.61 (t, 1H), δ3.03 (m, 2H), δ2.77(q, 4H), δ2.57 (t, 2H), δ2.01 (m, 2H), δ1.45 (m, 2H), δ1.21 (m, 2H),δ1.06 (t, 6H).

EMBODIMENT 212-(4-diethylaminobutyl)-malonato.cis-1,3-(2,2-hydroxymethyl)-propanediamineplatinum (II) phosphate Step 1, 2 and 3: Same as [Embodiment 1] Step 1,2 and 3 Step 4: 1,3-(2,2-hydroxymethyl)-propanediamine.diiodo-platinum(II)

KI (6.636 g, 40 mmol) solution (50 ml) was added to potassiumchloroplatinite (K₂PtCl₄) (2.074 g, 5 mmol) in water (50 ml), themixture was stirred and heated to 40˜60° C. away from light and oxygenfor 0.5˜2 h., and then 1,3-(2,2-hydroxymethyl)-propanediamine (671 mg, 5mmol) in water (50 ml) was added; the reaction mixture shall be keptunder this condition for 0.5˜2 h. Yellow solid product (2.163 g) wasobtained by suction filtration and washing successively with water (10ml×3 times) and diethyl ether (10 ml×3 times), the yield was 79.96%.

Elemental analysis: C10.37% (theoretical 10.29%); H2.49% (theoretical2.40%), N5.01% (theoretical 4.80%).

Step 5: 1,3-(2,2-hydroxymethyl)-propanediamine.dihydrate platinum (II)sulphate

Stirring Ag₂SO₄ (624 mg, 2 mmol) in water (30 ml),1,3-(2,2-hydroxymethyl)-propane diamine.diiodo-platinum (II) (1.162 g, 2mmol) was added and another part of water (40 ml) was added to thereaction mixture; the mixture was stirred and heated at 40˜60° C. for4˜8 h. After removing AgI deposit by suction, the filtrate was theaqueous solution of the title compound.

Step 6:2-(4-diethylaminobutyl)-malonato.cis-1,3-(2,2-hydroxymethyl)-propanediamine platinum (II) phosphate

2-(4-diethylaminobutyl)-malonate disodium salt solution was regulated tothe pH 5˜7 with H₃PO₄ (1M) and then aqueous1,3-(2,2-hydroxymethyl)-propanediamine.dihydrate platinum (II) sulphatewas poured into reaction mixture; the mixture was heated in water bathto 40˜60° C. for 4-8 h under the condition for N₂ protection. And thenadded 2.5 g silica into it; the mixture was stirred for 15 min andconcentrated to dry, the residue was purified by column chromatography(200-300 round) to afford the title compound (148 mg).

Embodiment 21 compound is soluble in water. The solubility is more than300 mg/ml. It can be easily converted into other types of organic orinorganic salts through free base. It may be but not limited tosulphate, mesylate, tartrate, succinateacetate, citrate, tosilate,fumarate, etc.

Free base elemental analysis: C34.48% (theoretical 34.41%), H5.80%(theoretical 5.91%), N7.49% (theoretical 7.53%).

¹HNMR (D₂O) (ppm): δ3.78 (s, 4H), δ3.61 (t, 1H), δ2.76 (s, 4H), δ2.69(t, 2H), δ2.56 (q, 4H), δ1.71 (m, 2H), δ1.44 (m, 2H), δ1.22 (m, 2H),δ1.03 (t, 6H).

EMBODIMENT 222-(4-diethylaminobutyl)-malonato.cis-1,4-(trans-2,3-cyclobutyl)-butanediamineplatinum (II) phosphate Step 1, 2 and 3: Same as [Embodiment 1] Step 1,2 and 3 Step 4: 2,3-diamino methyl cyclobutane.diiodo platinum (II)

KI (6.64 g, 40 mmol) solution was added to potassium chloroplatinite(K₂PtCl₄) (2.075 g, 5 mmol) in water (50 ml), the mixture was stirredand heated to 40˜60° C. away from light and oxygen for 0.5˜2 h., andthen 1,4-(trans-2,3-cyclobutyl)-butanediamine (571 mg, 5 mmol) in water(50 ml) was added; the reaction mixture shall be kept under thiscondition for 0.5˜2 h. Yellow solid product (2.251 g) was obtained bysuction filtration and washing successively with water (10 ml×3 times)and diethyl ether (10 ml×3 times), the yield was 79.96%.

Elemental analysis: C12.61% (theoretical 12.79%), H2.45% (theoretical2.49%), N5.11% (theoretical 4.97%).

Step 5: 2,3-diamino methyl cyclobutane.dihydrate platinum (II) sulphate

Stirring Ag₂SO₄ (625 mg, 2 mmol) in water (30 ml) which is placed in theboiling flask-3-neck of 100 ml, 2,3-diamino methyl cyclobutane.dihydrateplatinum(II) 1.122 g (2 mmol) was added and another part of water (40ml) was added to the reaction mixture; The mixture was stirred andheated at 40˜60° C. for 4˜8 h. After removing AgI deposit by suction,the filtrate was the aqueous solution of the product.

Step 6: 2-(4-diethylaminobutyl)-malonato.cis-2,3-diamino methylcyclobutane platinum (II) phosphate

2-(4-diethylamino butyl)-malonate disodium salt solution was regulatedto the pH 5˜7 with H₃PO₄ (1M) and then aqueous 1,4(trans-2,3cyclobutyl)-butanediamine.dihydrate platinum (II) sulphate was pouredinto reaction mixture; the mixture was heated in water bath to 40˜60° C.for 4-8 h under the condition for N₂ protection and then added 2.5 gsilica (200-300 rounds) into it, the mixture was stirred for 15 min andconcentrated to dry, the residue was purified by column chromatographyto afford the title compound (147 mg).

Embodiment 22 compound is soluble in water. The solubility is more than300 mg/ml. It can be easily converted into other types of organic orinorganic salts through free base. It may be but not limited tosulphate, mesylate, tartrate, succinateacetate, citrate, tosilate,fumarate, etc.

Free base elemental analysis: C37.79% (theoretical 37.92%), H6.36%(theoretical 6.13%), N7.76% (theoretical 7.81%).

¹HNMR (D₂O) (ppm): δ3.61 (t, 1H), δ2.76 (q, 4H), δ2.71 (t, 2H), δ2.23(d, 4H), δ1.96 (m, 2H), δ1.71 (m, 2H), δ1.45 (m, 4H), δ1.25 (m, 2H),δ1.13 (m, 2H), δ1.04 (t, 6H)

EMBODIMENT 23 2-(4-diethylaminobutyl)-malonato.cis-1,4-cyclohexyldiamine platinum (II) phosphate Step 1, 2 and 3: Same as [Embodiment 1]Step 1, 2 and 3 Step 4: 1,4-cyclohexyl diamine.diiodo-platinum (II)

KI (6.64 g, 40 mmol) solution was added to potassium chloroplatinite(K₂PtCl₄) (2.071 g, 5 mmol) in water (50 ml), the mixture was stirredand heated to 40˜60° C. away from light and oxygen for 0.5˜2 h., andthen 1,4-cyclohexyl diamine (572 mg, 5 mmol) in water (50 ml) was added;the reaction mixture was kept under this condition for 0.5˜2 h. Yellowsolid product (2.163 g) was obtained by suction filtration and washingsuccessively with water (10 ml×3 times) and diethyl ether (10 ml×3times), the yield was 76.84%.

Elemental analysis: C12.74% (theoretical 12.79%), H2.45% (theoretical2.49%), N5.17% (theoretical 4.97%).

Step 5: 1,4-cyclohexyl diamine.dihydrate platinum (II) sulphate

Stirring Ag₂SO₄ (623 mg, 2 mmol) in water (30 ml), 1,4-cyclohexyldiamine.diiodo-platinum (II) (1.125 g, 2 mmol) was added and anotherpart of water (40 ml) was added to the reaction mixture; the mixture wasstirred and heated at 40˜60° C. for 4˜8 h under the condition for N₂protection and keeping in dark space. After removing AgI deposit bysuction, the filtrate was the aqueous solution of the title compound.

Step 6: 2-(4-diethylamino butyl)-malonato.cis-1,4-cyclohexyl diamineplatinum (II) phosphate

2-(4-diethylamino butyl)malonate disodium salt solution was regulated tothe pH 5˜7 with H₃PO₄ (1M) and then 1,4-cyclohexyl diamine.dihydrateplatinum (II) sulphate was poured into reaction mixture; the mixture washeated in water bath to 40˜60° C. for 4-8 h under the condition for N₂protection. And then added 2.5 g silica into it; the mixture was stirredfor 15 min and concentrated to dry, the residue was purified by columnchromatography (200-300 rounds) to afford the title compound (151 mg).

Embodiment 23 compound is soluble in water. The solubility more than 300mg/ml. It can be easily converted into other types of organic orinorganic salts through free base. It may be but not limited tosulphate, mesylate, tartrate, succinateacetate, citrate, tosilate,fumarate, etc.

Free base elemental analysis: C37.81% (theoretical 37.92%), H5.97%(theoretical 6.13%), N8.02% (theoretical 7.81%).

¹HNMR (D₂O) (ppm): δ3.61 (t, 1H), δ2.79 (q, 4H), δ2.69 (t, 2H), 2.05 (m,2H), δ1.81 (m, 2H), δ1.78-1.51 (m, 8H), δ1.41 (m, 2H), δ1.23 (m, 2H),δ1.08 (t, 6H).

EMBODIMENT 24 2-(4-diethylaminobutyl)-malonato.cis-1,3-(2,2-(4-oxacyclohexyl))-propane diamine platinum(II) phosphate Step 1, 2 and 3: Same as [Embodiment 1] Step 1, 2 and 3Step 4: 1,3-(2,2-(4-oxacyclohexyl))-propane diamine.diiodo-platinum (II)

KI (6.64 g, 40 mmol) solution was added to potassium chloroplatinite(K₂PtCl₄) (2.071 g, 5 mmol) in water (50 ml), the mixture was stirredand heated to 40˜60° C. away from light and oxygen for 0.5˜2 h., andthen 1,3-(2,2-(4-oxacyclohexyl))-propane diamine (722 mg, 5 mmol) inwater (50 ml) was added; the reaction mixture was kept under thiscondition for 0.5˜2 h. Yellow solid product (2.547 g) was obtained bysuction filtration and washing successively with water (10 ml×3 times)and diethyl ether (10 ml×3 times), the yield was 85.91%.

Elemental analysis: C14.35% (theoretical 14.17%), H2.75% (theoretical2.70%), N4.72% (theoretical 4.72%).

Step 5: 1,3-(2,2-(4-oxacyclohexyl))-propane diamine.dihydrate platinum(II) sulphate

Stirring Ag₂SO₄ (623 mg, 2 mmol) in water (30 ml) which is placed in theboiling flask-3-neck of 100 ml, 1,3-(2,2-(4-oxacyclohexyl))-propanediamine.dihydrate platinum(II) (1.185 g, 2 mmol) was added and anotherpart of water (40 ml) was added to the reaction mixture; the mixture wasstirred and heated at 40˜60° C. for 4˜8 h under the condition for N₂protection and keeping in dark space. After removing AgI deposit bysuction, the filtrate was the aqueous solution of the title compound.

Step 6: 2-(4-diethylaminobutyl)-malonato.cis-1,3-(2,2-(4-oxacyclohexyl)-propane diamine platinum(II) phosphate

2-(2-diethylamino butyl)malonate disodium salt solution was regulated tothe pH 5˜7 with H₃PO₄ (1M) and then 1,3-(2,2-(4-oxacyclohexyl))-propanediamine.dihydrate platinum (II) sulphate was poured into reactionmixture; the mixture was heated in water bath to 40˜60° C. for 4-8 hwith N₂ protection. And then added 2.5 g silica (200-300 rounds) intoit; the mixture was stirred for 15 min and concentrated to dry, theresidue was purified by column chromatography to afford the titlecompound (167 mg).

Embodiment 24 compound is soluble in water. The solubility is more than300 mg/ml. It can be easily converted into other types of organic orinorganic salts through free base. It may be but not limited tosulphate, mesylate, tartrate, succinateacetate, citrate, tosilate,fumarate, etc.

Free base elemental analysis: C38.22% (theoretical 38.03%), H6.35%(theoretical 6.16%), N7.42% (theoretical 7.39%).

¹HNMR (D₂O) (ppm): δ3.71 (t, 4H), δ3.61 (t, 1H), δ2.77 (q, 4H), δ2.69(t, 2H), δ2.11 (s, 4H), δ1.88 (m, 2H), δ1.51 (t, 4H), δ1.40 (m, 2H),δ1.21 (m, 2H), δ1.03 (t, 6H).

EMBODIMENT 25 2-(4-diethylamino ebutyl)-malonato.cis-Bicyclic amylamineplatinum (II) acetate Step 1, 2 and 3: Same as [Embodiment 1] Step 1, 2and 3 Step 4: bicyclic amylamine.diiodo-diamine(II)

KI (6.640 g, 40 mmol) solution was added to potassium chloroplatinite(K₂PtCl₄) (2.075 g, 5 mmol) in water (50 ml), the mixture was stirredand heated to 40˜60° C. away from light and oxygen for 0.5˜2 h, and thenammonia water (50 ml) (containing 5 mmol ammonia) was added; thereaction mixture was kept under this condition for 0.5˜2 h. Light yellowsolid product (2.903 g) was obtained by suction filtration and washedsuccessively with water (10 ml×3 times) and diethyl ether (10 ml×3times); the yield was 93.8%.

Elemental analysis: C19.24% (theoretical 19.39%), H3.37% (theoretical3.55%), N6.58% (theoretical 6.79%).

Step 5: Bicyclic amylamine.dihydrate platinum (II) sulphate

Adding Ag₂SO₄ (625 mg, 2 mmol) in water (30 ml) which is placed in theboiling flask-3-neck of 100 ml, bicyclic amylamine.diiodo-platinum (II)(1.238 g, 2 mmol) was added and another part of water (40 ml) was addedto the reaction mixture; the mixture was stirred and heated at 40˜60° C.for 4˜8 h under the conditions for N₂ protection, and keep in darkplace. After removing AgI deposit by suction, the filtrate was theaqueous solution of the product.

Step 6: 2-(4-diethylamino butyl)-malonato.cis-bicyclic amylamineplatinum (II) acetate;

2-(4-diethylamino butyl)malonate disodium salt solution was regulated tothe pH 5˜7 with HAC (1M) and then aqueous cis-diamine.dihydrate platinum(II) sulphate was poured into reaction mixture; the mixture was heatedin water bath to 40˜75° C. for 4-6 h under the condition for N₂protection, the mixture was concentrated to certain volume and theresidue was standstill; The crystal type product (165 mg) was obtainedby suction.

Embodiment 25 compound is soluble in water. The solubility is more than300 mg/ml. It can be easily converted into other types of organic orinorganic salts through free base. It may be but not limited tosulphate, mesylate, tartrate, succinateacetate, citrate, tosilate,fumarate, etc.

Free base elemental analysis: C42.42% (theoretical 42.42%), H6.67%(theoretical 6.90%), N7.08% (theoretical 7.07%).

¹HNMR (D₂O) (ppm): δ3.52 (m, 1H), δ2.79 (q, 4H), δ2.67 (m, 2H), δ2.57(t, 2H), δ2.22 (m, 8H), δ1.80 (m, 2H), δ1.45 (m, 2H), δ1.36 (m, 8H),δ1.24 (m, 2H), δ1.05 (t, 6H).

EMBODIMENT 26 2-(4-diethylaminobutyl)-malonato.cis-ammonia.cyclopentylamine platinum (II) acetate Step1, 2 and 3: Same as [Embodiment 1] Step 1, 2 and 3 Step 4:ammonia.cyclopentylamine.diiodo-platinum(II)

KI (6.65 g, 40 mmol) solution was added to potassium chloroplatinite(K₂PtCl₄) (2.076 g, 5 mmol) in water (50 ml), the mixture was stirredand heated to 40˜60° C. away from light and oxygen for 0.5˜2 h, and thencyclopentylamine fluid (25 ml) (containing 2.5 mmol ammonia) was added;The reaction mixture was kept under this condition for 0.5˜2 h. Lightyellow solid product was obtained by suction filtration and washedsuccessively with water (10 ml×3 times) and diethyl ether (10 ml×3times); the title ammonia.cyclopentylamine.diiodo-platinum (II) (2.43 g)was obtained. The yield was 88.2%.

Elemental analysis: C10.76% (theoretical 10.89%), H2.31% (theoretical2.54%), N5.18% (theoretical 5.08%).

Step 5: ammonia.cyclopentylamine.dihydrate platinum (II) sulphate

Adding Ag₂SO₄ (625 mg, 2 mmol) in water (30 ml) which is placed in theboiling flask-3-neck of 100 ml. Ammonia.cyclopentylamine.dihydrateplatinum (II) (1.1 g, 2 mmol) was added and another part of water (40ml) was added to the reaction mixture; the mixture was stirred andheated at 40˜60° C. for 4˜8 h under the condition for N₂ protection andkeeping in dark space. After removing AgI deposit by suction, thefiltrate was the aqueous solution of the product.

Step 6: 2-(4-diethylamino butyl)-malonato.cis-.ammonia.cyclopentylamineplatinum (II) acetate

2-(4-diethylamino butyl)malonate disodium salt solution was regulated tothe pH 5˜7 with HAC (1M) and then ammonia.cyclopentylamine.dihydrateplatinum (II) sulphate was poured into reaction mixture; the mixture washeated in water bath to 40˜75° C. for 4-6 h, the mixture wasconcentrated to certain volume and the residue was standstill at roomtemperature; The title crystallization type compound (156 mg) wasobtained by suction.

Embodiment 26 compound is soluble in water. The solubility is more than300 mg/ml. It can be easily converted into other types of organic orinorganic salts through free base. It may be but not limited tosulphate, mesylate, tartrate, succinateacetate, citrate, tosilate,fumarate, etc.

Free base elemental analysis: C36.43% (theoretical 36.50%), H6.28%(theoretical 6.27%), N7.87% (theoretical 7.99%).

¹HNMR (D₂O) (ppm): δ3.62 (m, 1H), δ2.80 (q, 4H), δ2.67 (m, 1H), δ2.58(t, 2H), δ2.21 (m, 4H), δ1.80 (m, 2H), δ1.45 (m, 2H), δ1.36 (m, 4H),δ1.24 (m, 2H), δ1.05 (t, 6H).

EMBODIMENT 27 2-(4-diethylaminobutyl)-malonato.cis-(2-aminomethyl.cyclopentylamine) platinum (II)acetate Step 1, 2 and 3: Same as [Embodiment 1] Step 1, 2 and 3 Step 4:2-aminomethyl.cyclopentylamine.diiode-platinum(II)

KI (6.65 g, 40 mmol) solution was added to potassium chloroplatinite(K₂PtCl₄) (2.075 g, 5 mmol) in water (50 ml), the mixture was stirredand heated to 40˜60° C. away from light and oxygen for 0.5˜2 h under thecondition for N₂ protection and keeping in dark space, and then2-aminomethyl.cyclopentylamine solution (included 571 mg of ammonia) 5mmol in water (50 ml) was added; The reaction mixture was kept underthis condition for 0.5˜2 h. Yellow solid product (2.58 g) was obtainedby suction filtration and washed successively with water (10 ml×3 times)and diethyl ether (10 ml×3 times), the yield was 92.31%.

Elemental analysis: C12.71% (theoretical 12.88%), H1.72% (theoretical1.79%), N5.11% (theoretical 5.01%).

Step 5: 2-aminomethyl-cyclopentylamine.dihydrate platinum (II) sulphate

Stirring Ag₂SO₄ (625 mg, 2 mmol) in water (30 ml) which was placed inthe boiling flask-3-neck of 100 m,2-aminomethyl-cyclopentylamine.diiodo-platinum (II) (1.12 g, 2 mmol) wasadded and another part of water (40 ml) was added to the reactionmixture, the mixture was stirred and heated at 40˜60° C. for 4˜8 h underthe condition for N₂ protection and keeping in dark space. Afterremoving AgI deposit by suction, the filtrate was the aqueous solutionof the product.

Step 6: 2-(4-diethylaminobutyl)-malonato.cis-(2-aminomethyl-cyclopentylamine) platinum (II)acetate

2-(4-diethylamino butyl)malonate disodium salt solution was regulated tothe pH 5˜7 with HAC (1M) and then cis-2-aminomethyl-cyclopentylamine.dihydrate platinum (II) sulphate was poured intoreaction mixture; the mixture was heated in water bath to 40˜75° C. for4-6 h with N₂ protection, the mixture was concentrated to certain volumeand the residue was standstill at room temperature; The crystal typeproduct (147 mg) was obtained by suction.

Embodiment 27 compound is soluble in water. The solubility is more than300 mg/ml. It can be easily converted into other types of organic orinorganic salts through free base. It may be but not limited tosulphate, mesylate, tartrate, succinateacetate, citrate, tosilate,fumarate, etc.

Free base elemental analysis: C37.81% (theoretical 37.92%), H6.25%(theoretical 6.13%), N7.85% (theoretical 7.81%).

¹HNMR (D₂O) (ppm): δ3.61 (m, 1H), δ2.81 (q, 4H), δ2.69 (m, 1H), δ2.60(d, 2H), δ2.53 (t, 2H), δ2.31 (m, 1H), δ2.18 (m, 2H), δ1.79 (m, 2H),δ1.45 (m, 2H), δ1.35 (m, 4H), δ1.22 (m, 2H), δ1.03 (t, 6H).

EMBODIMENT 28 2-(4-diethylamino butyl)-malonato.cis-.ammonia.piperidineplatinum (II) acetate Step 1, 2 and 3: Same as [Embodiment 1] Step 1, 2and 3 Step 4: Ammonia.piperidine.diiodo-platinum (II)

KI (6.65 g, 40 mmol) solution was added to potassium chloroplatinite(K₂PtCl₄) (2.075 g, 5 mmol) in water (50 ml), the mixture was stirredand heated to 40˜60° C. away from light and oxygen for 0.5˜2 h., andthen piperidine solution (ammonia 2.5 mmol) 25 ml was added; thereaction mixture was kept under this condition for 0.5˜2 h. Yellow solidproduct (ammonia.piperidine.diiodo-platinum) (2.40 g) was obtained bysuction filtration and washed successively with water (10 ml×3 times)and diethyl ether (10 ml×3 times), the yield was 87.1%. Elementalanalysis: C10.71% (theoretical 10.89%), H2.42% (theoretical 2.54%);N5.23% (theoretical 5.08%).

Step 5: Ammonia.piperidine.dihydrate platinum (II) sulphate

Stirring Ag₂SO₄ (625 mg, 2 mmol) in water (30 ml) which is placed in theboiling flask-3-neck of 100 ml, ammonia.piperidine.diiodo-platinum (II)(1.09 g, 2 mmol) was added and another part of water (40 ml) was addedto the reaction mixture; the mixture was stirred and heated at 40˜60° C.for 4˜8 h, N₂ protection and light-proof. After removing AgI deposit bysuction, the filtrate was the aqueous solution of the product.

Step 6: 2-(4-diethylamino butyl)-malonato.cis-.ammonia.piperidineplatinum (II) acetate

2-(4-diethylamino butyl)malonate disodium salt solution was regulated tothe pH 5˜7 with HAC (1M) and then ammonia.piperidine.dihydrate platinum(II) sulphate water solution was poured into reaction mixture; themixture was heated in water bath to 40˜75° C. for 4˜6 h. Under N₂protection; after filtration, the filtrate was concentrated to a certainvolume and should be at a standstill; crystalline-type product (160 mg)was obtained.

Embodiment 28 compound is soluble in water. The solubility is more than300 mg/ml. It can be easily converted into other types of organic orinorganic salts through free base. It may be but not limited tosulphate, mesylate, tartrate, succinateacetate, citrate, tosilate,fumarate, etc.

Free base elemental analysis: C36.37% (theoretical 36.50%), H6.36%(theoretical 6.27%), N7.95% (theoretical 7.99%).

¹HNMR (D₂O) (ppm): δ3.61 (m, 1H), δ2.79 (q, 4H), δ2.67 (t, 4H), δ2.58(t, 2H), δ2.19 (m, 4H), δ1.81 (m, 2H), δ1.40 (m, 2H), δ1.29 (m, 2H),δ1.21 (m, 2H), δ1.03 (t, 6H).

EMBODIMENT 29 2-(4-trimethylamino butyl)-malonatocis-(1,2-trans-cyclohexanediamine) platinum(II) tosilate Step 1: Same as[Embodiment 1] Step 1 Step 2: 2-(4-trimethyl aminobutyl))-diethylmalonate

To the mixture of 4-brombutyl-Diethyl malonate (117.9 g, 0.4 mol),anhydrous K₂CO₃ (55.5 g, 0.4 mol) in acetonitrile (500 ml),trimethylamine (59.0 g, 1.0 mol) was added into mixture which was thenheated at 45˜60° C. for 2-6 h; insoluble substance is filtered out andthe filtrate was concentrated in vacuo; the residues was dissolved with1000 ml ethyl acetate; organic phase was washed with saturate NaClaqueous solution (250 ml×3 times) and dried over anhydrous MgSO₄overnight; after removal of solvent in vacuo, light yellow oil (99.0 g)was obtained; and then added water 50 ml and Ag₂O 50 g, centrifugal andsupernatant respectively extract three times with ethyl acetate (300ml), and then the extracting solution is merged, remove ethyl acetate byotary evaporation to obtain product 45.6 g, the yield was 39.18%.

Step 3: 2-(4-trimethyl aminobutyl))-malonate disodium salt

2M NaOH solution (obtained from the NaOH of 212 mg or 5 mmol plus waterof 2.5 mL) was added to 2-(4-trimethyl aminobutyl))-diethyl malonate(582 mg, 2 mmol) in 20 mL flasks; and the mixture was stirred at roomtemperature for 45˜60 h, 2-(4-trimethyl aminobutyl))malonate disodiumsalt solution was obtained.

Step 4, 5: Same as [Embodiment 3] Step 4, 5 Step 6: 2-(4-trimethylaminobutyl)-malonato.cis(1,2-trans-cyclohexanediamine)-platinum (II) tosilate

2-(4-trimethyl aminobutyl)-malonate disodium salt (2 mmol) solution wasregulated to the pH 5˜7 with p-toluenesulfonic acid (1M) and thenaqueous tran-cyclohexanediamine-dihydrate platinum (II) sulphate waspoured into reaction mixture; the mixture was heated in water bath to40˜60° C. for 4-8 h under the condition for N₂ protection. And thenadded 2.5 g silica into it; the mixture was stirred for 15 min andconcentrated to dry, the residue was purified by column chromatography(200-300 rounds) to afford the title compound (150 mg).

Embodiment 29 compound is soluble in water. The solubility is more than300 mg/ml. It can be easily converted into other types of organic orinorganic salts through free base. It may be but not limited tosulphate, mesylate, tartrate, succinateacetate, citrate, tosilate,fumarate, etc.

Free base elemental analysis: C35.70% (theoretical 35.42%), H6.21%(theoretical 6.09%), N7.79% (theoretical 35.42%).

¹HNMR (D₂O) (ppm): δ3.62 (m, 1H), δ2.79 (s, 9H), δ2.65 (m, 2H), δ2.45(t, 2H), δ1.80 (m, 4H), δ1.46 (m, 4H), δ1.25 (m, 4H), δ1.01 (m, 2H).

EMBODIMENT 30-65

Refer to the above synthesis procedures more compounds in below table 1and table 2 were produced, the LD₅₀ and the IC₅₀ of anti-lung lungcancer A549 according to test 1 and test 2 methods were also shown intable 1 and table 2.

The ligands —NH₂—R₄ and NH₂—R₅ of the above Formula I are expressed as—R_(a) and —R_(b) (table 1)

TABLE 1 Compounds with formula I structure, their LD₅₀, mass spectra andIC₅₀ of anti-lung cancer A549 Mass spec- LD₅₀ tro- Com- (mmol/ metryIC₅₀ pound R₁— R₂— —R₃— —R_(a) —R_(b) kg) (MS) (mM) 30 C₂H₅— CH₃—

—NH₃ —NH₃ 0.759 474   0.012 31 C₂H₅— CH₃—

0.732 554   0.005 32 C₃H₇— C₃H₇—

0.845 578   0.015 33

—C₄H₈—

0.826 548   0.007 34

CH₃— —C₄H₈—

0.905 552   0.011 35

—C₄H₈—

0.762 534   0.004 36

0.713 584.5 0.007 37

—C₄H₈—

0.825 564   0.009 38

—C₄H₈—

0.818 550   0.006 39

—C₄H₈—

0.711 594   0.006 40 C₂H₅— C₂H₅— —C₄H₈—

0.683 570   0.021 41

—C₄H₈—

0.675 598.5 0.013 42

—C₄H₈—

0.826 618   0.005 43

CH₃— —C₄H₈—

0.841 564   0.005 44 CH₃— CH₃— —C₄H₈—

0.857 496   0.024 45 CH₃— CH₃— —C₄H₈—

0.834 498   0.031 46 CH₃— CH₃— —C₄H₈—

0.823 468   0.027 47 CH₃— CH₃— —C₄H₈—

0.815 482   0.023 48 CH₃— CH₃— —C₄H₈—

0.831 496   0.031 49 CH₃— CH₃— —C₄H₈—

0.817 510   0.045 50 C₃H₇— C₃H₇—

0.773 592   0.012 51

—C₄H₈—

0.654 552   0.026 52 HO—CH2— CH₃— —C₄H₈— —NH₃

0.687 500   0.041 53

CH₃— —C₄H₈— —NH₃ —NH₃ 0.874 456   0.054 54 C₂H₅— CH₃—

0.792 540   0.015 55 C₂H₅— C₂H₅— —C₄H₈—

0.852 594   0.061 56

—C₄H₈—

0.816 618   0.057 57 CH₃—

—C₄H₈—

0.613 586   0.032 58 CH₃—

—C₄H₈—

0.607 620.5 0.037 59 CH₃—

—C₄H₈— —NH₃ —NH₃ 0.598 558.5 0.068 60 C₄H₉— CH₃— —C₄H₈—

0.875 552   0.009 61

CH₃— —C₄H₈—

0.837 552   0.014 62 C₂H₅— C₂H₅— —C₄H₈— —NH₂— CH₂— CH═ CH—CH₃—NH₂—CH₂—C≡C— CH₂—CH₃ 0.796 564   0.023 63 C₂H₅— C₂H₅— —C₄H₈— —NH₂—(CH₂)₂— CH₃

0.804 567   0.025 64 C₂H₅— C₂H₅— —C₄H₈— —NH₂— CH₂— —NH₂—CH₂—N— (C₂H₅)₂0.675 587   0.017

The ligands —NH₂—R₄ and NH₂—R₅ of the above Formula II are expressed as—R_(a) and —R_(b) (table 2)

TABLE 2 Compounds with formula II structure, their LD₅₀, mass spectraand IC₅₀ of anti-lung cancer A549 Mass LD₅₀ spectro- com- VALUE ometryIC₅₀ pound R₀— R₁— R₂— R₃— —Ra —R_(b) (mmol/kg) (MS) (mM) 65 CH₃— C₄H₉—CH₃— —C₄H₈—

0.615 627 0.016 66 C₂H₅— C₂H₅— C₂H₅— —C₄H₈— —NH₃ —NH₃ 0.677 487 0.020 67C₂H₅— C₂H₅— C₂H₅— —C₄H₈— —NH₂—(CH₂)₃—CH₂ —NH₂—(CH₂)₃—CH₂ 0.802 599 0.02768 C₂H₅— C₂H₅— C₂H₅— —C₄H₈—

0.714 590 0.019

Phosphates of equal molecular of the above Embodiment compounds 30-68and phosphoric acid were easily dissolved in water, their solubilitywere more than 300 mg/ml, and the pH of their aqueous solution were 5˜7.

Test 1: Acute Toxic Effect of Platinum Complex on Normal Mice

Kunming mice at 4˜6 weeks old and at the weight of 18˜22 g were taken,50% male and 50% female. Embodiment platinum compound was dissolved with5% glucose solution. Single intravenous administration (control:carboplatin and cisplatin) was made at different doses. Mortality andtoxicity were observed after administration. Totally observing 14 days,LD₅₀ value was calculated with Bliss method according to mortality. Theresults are shown in Table 3:

TABLE 3 Results of Intravenous Injection of Cisplatin, Carboplatin andEmbodiment Platinum Compounds to Rat LD₅₀: LD₅₀ VALUE Embodiment LD₅₀value Compound (mmol/kg) compound (mg/kg) Cisplatin 0.044 Compound 150.872 Carboplatin 0.336 Compound 16 0.767 Compound 1 0.746 Compound 170.729 Compound 2 0.797 Compound 18 0.810 Compound 3 0.815 Compound 190.767 Compound 4 0.823 Compound 20 0.834 Compound 5 0.845 Compound 210.757 Compound 6 0.756 Compound 22 0.779 Compound 7 0.778 Compound 230.831 Compound 8 0.801 Compound 24 0.769 Compound 9 0.725 Compound 250.722 Compound 10 0.791 Compound 26 0.722 Compound 11 0.803 Compound 270.755 Compound 12 0.729 Compound 28 0.725 Compound 13 0.816 Compound 290.638 Compound 14 0.866

Conclusion: The acute toxicity of the compounds at the same molarconcentration in the Embodiment 1-60 is much smaller than cisplatin andcarboplatin.

Test 2: Cytotoxcity Effects of the Embodiment Platinum Compounds onTumor Cell

The toxic action of Embodiment platinum compounds was observed on tumorcells by MTT colorimetric method. Several kinds of tumor cells inexponential growth phase were prepared into single cell suspension,inoculated on 96 pore plat at the density of 4×10⁴/hole, cultivated for24 hours to enable to adhere to wall with 1640 culture medium containing10% fetal calf serum (complete medium) at 37° C.; The final culturevolume was 100 μl. Cell morphology was observed after culture for 24hours. For the dosage of platinum compounds, since IC₅₀ values of cellsare different, the following concentrations are determined throughpretest: appropriate adjustment on 200, 60, 20, 6, 2, 0.6 μg/mlcisplatin, 200, 60, 20, 6, 2, 0.6 μg/ml carboplatin, and Embodimentplatinum compounds depending on the sensitivity to each cell. Theresults are shown in Table 4-9 below:

TABLE 4 The cytotoxicity (IC₅₀) of different test platinum compounds todifferent cell lines The IC₅₀ (n = 6) of chemotherapeutic drugs todifferent cell lines IC₅₀ (mM) Cell lines Carboplatin Cisplatin Compound1 Compound 2 Compound 3 Compound 4 Breast cancer 0.103 0.012 0.006 0.0100.007 0.005 MCF-7 Breast cancer 0.255 0.015 0.009 0.015 0.021 0.016MCF-7 cisplatin resistance strain Lung cancer 0.232 0.016 0.009 0.0320.008 0.021 A549 Lung cancer 0.055 0.0053 0.003 0.011 0.006 0.008 H292

TABLE 5 The cytotoxicity (IC₅₀) of different test platinum compounds todifferent cell lines The IC₅₀ (n = 6) of chemotherapeutic drugs todifferent cell lines IC₅₀ (mM) Cell lines Carboplatin Cisplatin Compound5 Compound 6 Compound 7 Compound 8 Compound 9 Alveolar 0.037 0.00330.002 0.003 0.004 0.005 0.002 Epithelial cells BEAS-2B Lung 0.038 0.0450.018 0.041 0.021 0.025 0.050 cancerLewis Lung 0.087 0.015 0.009 0.0020.010 0.016 0.014 cancerSW480 Lung 0.055 0.0053 0.006 0.007 0.004 0.0040.008 cancerH292

TABLE 6 The cytotoxicity (IC₅₀) of different test platinum compounds todifferent cell lines The IC₅₀ (n = 6) of chemotherapeutic drugs todifferent cell lines IC₅₀ (mM) Compound Compound Compound CompoundCompound Cell lines Carboplatin Cisplatin 10 11 12 13 14 Alveolar 0.0370.0033 0.003 0.002 0.008 0.003 0.005 epithelial cells BEAS-2B Lung 0.0380.045 0.051 0.049 0.018 0.059 0.036 cancerLewis Lung 0.087 0.015 0.0130.021 0.018 0.015 0.017 cancerSW480 Lung 0.055 0.0053 0.003 0.005 0.0060.009 0.012 cancerH292

TABLE 7 The cytotoxicity (IC₅₀) of different test platinum compounds todifferent cell lines The IC₅₀ (n = 6) of chemotherapeutic drugs todifferent cell lines IC₅₀ (mM) Compound Compound Compound CompoundCompound Cell lines Carboplatin Cisplatin 15 16 17 18 19 Gastric 0.1950.00899 0.011 0.010 0.016 0.022 0.013 carcinoma ST Stomach cancer 0.6250.0025 0.003 0.004 0.005 0.002 0.005 MGC803 Lung cancer 0.087 0.0150.018 0.013 0.007 0.014 0.023 SW480 Lung 0.055 0.0053 0.010 0.005 0.0040.008 0.006 cancerH292

TABLE 8 The cytotoxicity (IC₅₀) of different test platinum compounds todifferent cell lines The IC₅₀ (n = 6) of chemotherapeutic drugs todifferent cell lines IC₅₀ (mM) Compound Compound Compound CompoundCompound Cell lines Carboplatin Cisplatin 20 21 22 23 24 Gastric 0.1950.00899 0.011 0.013 0.014 0.008 0.006 carcinoma ST Stomach cancer 0.6250.0025 0.004 0.005 0.007 0.005 0.003 MGC803 Asophagus 0.052 0.073 0.0170.015 0.102 0.066 0.052 cancer ECA109 Lung 0.055 0.0053 0.005 0.0120.005 0.014 0.003 cancerH292

TABLE 9 The cytotoxicity (IC₅₀) of different test platinum compounds todifferent cell lines The IC₅₀ (n = 6) of chemotherapeutic drugs todifferent cell lines IC₅₀ (mM) Compound Compound Compound CompoundCompound Cell lines Carboplatin Cisplatin 25 26 27 28 29 Testis cell ST0.195 0.00899 0.007 0.011 0.013 0.061 0.008 Gastric 0.625 0.0025 0.0030.001 0.005 0.006 0.002 carcinoma MGC803 Asophagus 0.052 0.073 0.0290.091 0.054 0.046 0.025 cancer ECA109 Lung cancer 0.055 0.0053 0.0060.004 0.004 0.011 0.007 H292

The tables 1, 2, 4-9 showed that embodiment compounds 1-29 haveequivalent or stronger cytotoxic effects in vitro with cisplatin, andstronger than carboplatin.

Preparations Example 1 Preparation of Injection

Prescription 1

compound in Embodiment 2 10 g Glucose 50 g Add water for injection to1000 ml To produce into 1000

Process: 10 g compound in Embodiment 2 and 50 g glucose was dissolved in1000 ml injection water at normal temperature in 2000 ml glassware,after filtration with 0.22 μm microporous membrane, the filtration wascharged into 1 ml ampoule to obtain the product at the specification of10 mg/ml.

Prescription 2

compound in example 6 10 g Glucose 50 g Add water for injection to 1000ml To produce into 1000

Process: 10 g compound in Embodiment 6 and 50 g glucose was dissolvedinto 1000 ml injection water at normal temperature in 1000 ml glassware,after filtration with 0.22 μm microporous membrane, the filtration wascharged into 2 ml penicillin bottle to afford the product at thespecification of 10 mg/bottle.

Preparations Example 2 Preparation of Refrigerated Powder for InjectionPrescription 1

compound in Embodiment 9 10 g Mannitol 50 g Add water for injection to1000 ml To produce into 1000

Process: 10 g compound in Embodiment 9 and 50 g Mannitol were dissolvedinto 1000 ml injection water at normal temperature in 1000 ml glassware,after filtration with 0.22 μm microporous membrane, the filtration wascharged into 2 ml penicillin bottle, 1 ml solution in each bottle, andthen refrigerated to obtain the product at the specification of 10mg/bottle.

Prescription 2

compound in Embodiment 11 20 g Mannitol 50 g Add water for injection to1000 ml To produce into 1000

Process: 20 g compound in Embodiment 11 and 50 g Mannitol was dissolvedinto 1000 ml injection water at normal temperature in 1000 ml glassware,after filtration with 0.22 μm microporous membrane, the filtration wascharged into 2 ml penicillin bottle, 1 ml solution in each bottle, andthen refrigerated to obtain the product at the specification of 20mg/bottle.

Prescription 3

compound in Embodimen13 50 g Add water for injection to 1000 ml toproduce into 1000

Process: 50 g compound in Embodiment 13 was dissolved into 1000 mlinjection water at normal temperature in 1000 ml glassware, afterfiltration with 0.22 μm microporous membrane, the filtration was chargedinto 2 ml penicillin bottle, 1 ml solution in each bottle, and thenrefrigerated to obtain the product at the specification of 50 mg/bottle.

1. Compounds of formula A,

or pharmaceutically acceptable salts, solvates, stereoisomers, orprodrugs thereof, wherein: R₀ may or may not exist. When R₀ exists, itis selected from alkyl, naphthenic base, alkoxy alkyl, alkyl aminoalkyl, heterocycle, alkenyl and chain alkynyl, which are unsubstituted;or optionally substituted by halogen, hydroxyl, alkoxy, alkyl, alkoxyalkyl, naphthenic base, heterocycle, aryl, provided that R₀ do notcontain unsaturated bond, or R₀ contains unsaturated bond, while theatom of the unsaturated bond cannot be directly connected with nitrogenatom; and then formula A is quaternary ammonium, while when R₀ does notexist, formula A is tertiary amine; R₁ and R₂ may be the same ordifferent, and selected from hydrogen, alkyl, naphthenic base, alkoxyalkyl, alkyl amino alkyl, heterocycle, alkenyl, and alkynyl, which areunsubstituted; or optionally substituted by halogen, hydroxyl, alkoxy,alkyl, alkoxy alkyl, naphthenic base, heterocycle, and aryl, providedthat R₁ and R₂ do not contain unsaturated bond, or R₁ and/or R₂ containsunsaturated bond, while the atom of the unsaturated bond cannot bedirectly connected with nitrogen atom; R₁, R₂ and the atoms connectedwith them may form a closed saturated or unsaturated heterocycle. Forexample, it can be ternary, quaternary, pentabasic, hexahydric,heptabasic or octatomic ring; the above may be optionally condensed withother rings and may be optionally substituted by halogen, hydroxyl,alkoxy, alkyl, alkoxy alkyl, naphthenic base, heterocycle, and aryl,provided that the atom connected with nitrogen atom is saturated carbonatom; R₃ is the alkyl or naphthenic base of C₄, it can be substituted byone or more alkoxy, hydroxyl, alkyl, halogen, halogenated alkyl, alkoxyalkyl, and heterocycle. R₄ and R₅ may be the same or different, andselected from: hydrogen, hydroxyl, alkyl, naphthenic base, alkoxy,alkoxy alkyl, heterocycle, alkenyl, chain alkynyl; wherein alkyl,alkenyl, chain alkynyl, naphthenic base, alkoxy alkyl, alkyl amino alkyland heterocycle can be unsubstituted or optionally substituted,preferably substituted by halogen, hydroxyl, alkoxy, straight chain orbranched-chain alkyl, alkoxy alkyl, naphthenic base and heterocycle; R₄,R₅ and the atoms connected with them may form a closed ring, which maybe quaternary, pentabasic, hexahydric, heptabasic or octatomic ring; theabove rings may be optionally condensed with other rings and may beoptionally substituted.
 2. Compounds according to claim 1, wherein: R₃is the alkyl of C₄, it can be substituted by one or more alkoxy,hydroxyl, alkyl, and the above mentioned alkoxy is selected from:methoxyl, oxethyl, propoxy, and isopropoxy; the above mentioned alkylselected from methyl, ethyl and isopropyl.
 3. Compounds according toclaim 1, wherein: R₃ is the naphthenic base of C₄, it can be substitutedby one or more alkoxy, hydroxyl, alkyl, and the stated alkoxy isselected from methoxyl, oxethyl, propoxy, isopropoxy; the abovementioned alkyl is selected from methyl, ethyl, isopropyl.
 4. Compoundsaccording to claim 1, wherein: R₁ and R₂ are selected independently fromhydrogen, methyl, ethyl or propyl; or the closed ring formed by R₁ andR₂ and their connected atoms, which can be pyrrole ring or pyridine ringand the above rings can be substituted optionally.
 5. Compoundsaccording to claim 1, wherein R₄ and R₅ are hydrogen.
 6. Compoundsaccording to claim 1, wherein the structure refer to formula C:

And the above structure can be optionally substituted; R₆ is (CH₂)_(n),wherein n=1-6, preferably 3-5, the most preferably 4, wherein some —CH₂—may be substituted by —O—; wherein one or more hydrogens of (CH₂)_(n)are optionally substituted by fluorine, alkyl, hydroxyl or alkoxy, andheterocycle; the preferred compounds are (±)trans-1,2-cyclohexanediamine platinum (II),trans-1,2-cyclopentamethylenediamine platinum (II),trans-1,2-cyclobutanediamine platinum (II) and trans-1,2-cyclopropanediamine platinum (II); R₇ is (CH₂)_(n), wherein n=0-3, preferably n=0-2;wherein some —CH₂— may be substituted by —O—; wherein one or morehydrogens of (CH₂)_(n) are optionally substituted by halogen, alkyl,hydroxyl, hydroxyalkyl, alkoxy, and heterocycle; R₈ and R₉ are selectedfrom hydrogen, halogen, hydroxyl, hydroxyalkyl, alkyl, alkoxy andheterocycle; R₈ and R₉ may be the same or different, preferablyhydroxymethyl (formula F); R₁₀ and R₁₁ are selected from hydrogen,halogen, hydroxyalkyl, alkyl, alkoxy, heterocycle, etc.; R₁₀ and R₁₁ maybe the same or different, preferably hydroxymethyl; R₁₂ is (CH₂))_(n),wherein n=2-4, wherein some —CH₂— may be substituted by —O—; one or morehydrogens of (CH₂)_(n) may be substituted by halogen, alkyl, hydroxyl,alkoxy or heterocycle or alkoxy, etc.; R₁₃ is —CH₂— or —O—, —CH₂— ispreferably; R₁₄ is selected from hydrogen, halogen, alkyl, alkoxy,heterocycle, hydroxyalkyl or hydroxyl; R₁₄ is hydrogen preferably; R₁₅is selected from: (CH₂)_(n), wherein n=1-3, —CH2-O— or —O—; wherein oneor more hydrogens of (CH₂)_(n) may be substituted by alkyl, alkoxy,heterocycle, hydroxyl, or hydroxyalkyl; preferably —CH₂—O—CH₂—. 7.Compounds according to claim 6 is as follows:


8. Compounds or pharmaceutical acceptable salts, solvates, stereoisomersor prodrugs thereof according to claim 1, wherein said compounds areselected from the group consisting of: Compound 1: 2-(4-diethylaminobutyl)-malonato.Cis-diamine platinum (II) acetate; Compound 2:2-(4-diethylamino butyl)-malonato.Cis-(1,2-ethylenediamine) platinum(II) tosilate; Compound 3: 2-(4-diethylaminobutyl)-malonato.Cis-(1,2-trans-cyclohexanediamine) platinum (II)tosilate; Compound 4: 2-(4-(1-piperidyl)-butyl)-malonato.Cis-diamineplatinum (II) phosphate; Compound 5:2-(4-(1-tetrahydropyrrolo)-butyl)-malonato.Cis-diamine platinum (II)phosphate; Compound 6: 2-(3-dimethylaminocyclobutyl)-malonato.Cis-diamine platinum (II) mesylate; Compound 7:2-(4-di-n-propylamino butyl)-malonato.Cis-diamine platinum (II)phosphate; Compound 8: 2-(3-methyl-4-diethylaminobutyl)-malonato.Cis-diamine platinum (II) acetate; Compound 9:2-(4-(1-piperidyl)-butyl)-malonato.Cis-(1,2-trans-cyclohexanediamine)platinum (II) tosilate; Compound 10:2-(4-(2-methyl-1-tetrahydropyrrolo)-butyl)-malonato.Cis-diamine platinum(II) phosphate; Compound 11: 2-(4-aminobutyl)-malonato.Cis-(1,2-trans-cyclohexanediamine) platinum (II)phosphate; Compound 12: 2-(4-ethylaminobutyl)-malonato.Cis-(1,2-trans-cyclohexanediamine) platinum (II)phosphate; Compound 13: 2-(4-N-methyl-isopropylaminobutyl)-malonato.Cis-(1,2-trans-cyclohexanediamine) platinum (II)acetate; Compound 14: 2-(4-diethylaminobutyl)-malonato.Cis-(1,2-trans-cyclopentanediamine) platinum (II)phosphate; Compound 15: 2-(4-diethylaminobutyl)-malonato.Cis-(1,2-trans-cyclobutanediamine) platinum (II)succinate; Compound 16: 2-(4-diethylaminobutyl)-malonato.Cis-(1,2-trans-cyclopropanediamine) platinum (II)phosphate; Compound 17: 2-(4-diethylaminobutyl)-malonato.Cis-(1,2-ethylenediamine) platinum (II) tosilate;Compound 18: 2-(4-diethylamino butyl)-malonato.Cis-(1,3-propanediamine)platinum (II) phosphate; Compound 19: 2-(4-diethylaminobutyl)-malonato.Cis-(1,4-butanediamine) platinum (II) phosphate;Compound 20: 2-(2-diethylamino butyl)-malonato.Cis-1,2-(1,2-bishydroxymethyl)-ethylene diamine platinum (II) phosphate; Compound 21:2-(4-diethylamino butyl)-malonato.Cis-1,3-(2,2-hydroxymethyl)-propanediamine platinum (II) phosphate; Compound 22: 2-(4-diethylaminobutyl)-malonato.Cis-1,4-(trans-2,3-cyclobutyl)-butanediamine platinum(II) phosphate; Compound 23: 2-(4-diethylaminobutyl)-malonato.Cis-(1,4-cyclohexyldiamine) platinum (II) phosphate;Compound 24: 2-(4-diethylaminobutyl)-malonato.Cis-1,3-(2,2-(4-oxacyclohexyl))-propane diamine platinum(II) phosphate; Compound 25: 2-(4-diethylaminobutyl)-malonato.Cis-dicyclopentylamine platinum (II) acetate; Compound26: 2-(4-diethylamino butyl)-malonato.Cis-.ammonia.cyclopentylamineplatinum (II) acetate; Compound 27: 2-(4-diethylaminobutyl)-malonato.Cis-.(2-aminomethyl-cyclopentylamine) platinum (II)acetate; Compound 28: 2-(4-diethylamino butyl)-malonato.Cis-.ammoniapiperidine platinum (II) acetate; Compound 29: 2-(4-trimetlylaminobutyl)-malonato.Cis-(1,2-trans-cyclohexanediamine) platinum (II)tosilate.
 9. Compounds according to claim 1, wherein the said compoundsare in the form of pharmaceutically acceptable salts.
 10. Compoundsaccording to claim 9: the pharmaceutically acceptable salts are selectedfrom nitrate, carbonate, sulphate, phosphate, mesylate,trifluoromethanesulfonic salt, tosilate, benzene sulfonate, acetate,fumarate, tartrate, oxalate, maleate, malate, succinate, lactate,citrate, glutamate, or aspartate.
 11. Pharmaceutical compositions,containing the compounds in claim 1 and pharmaceutically acceptablecarriers.
 12. Pharmaceutical compositions according to claim 11, thesaid compositions are in any appropriate dosage forms. 13.Pharmaceutical compositions according to claim 11, it may or may notcontain one or more of other drugs suit for the treatment of cancers.14. The preparation methods for compounds in claim 1, including thefollowing steps: (1) Potassium chloroplatinite was added into water andthe mixture was stirred at room temperature; potassium iodide wasdissolved by water and then added into above solution to react away fromlight in water bath under nitrogen charging condition; (2) R₄NH₂ wasdissolved by water and added dropwise into the reaction solution in (1);the mixture was reacted in water bath condition; (3) After cooling downthe above reaction mixture below room temperature, R₅NH₂ was dissolvedby water and then added dropwise to the reaction mixture (2) to react inwater bath; yellow deposit in large quantity was generated in themixture; after cooling down the mixture below room temperature; diiododiamine platinum (II) was obtained through suction filtration andwashing; (4) Ag₂SO₄ was added in water and then stirred; the abovediiodo diamine platinum (II) was added into the reaction mixture andthen water was added; the mixture was stirred in water bath conditionaway from light and N₂ is charged; dihydrol diamine platinum (II) sufatewas obtained by suction filtration; (5) Diethyl malonate and Br—R₃—Brwere put into a flask. K₂CO₃ and tetrabutylammonium bromide were addedinto the flask, then the mixture was stirred and heated; after removalof solid by suction filtration and washing, collect the filtrate andwash the organic layer, dry it, and decompress the distillation solventand collect the distillation; (6) 2-Br—R₃-diethyl malonate was put intoa flask, then anhydrous K₂CO₃ was added in and stirred withacetonitrile; R₁—NH—R₂ or R₁—N(R₀)—R₂ was added into reaction mixture;the mixture was stirred and heated; After filtering out insolublesubstance of the mixture, the filtrate was pumped dry and residue wasdissolved in organic solvent and washed with aqueous solution; after drythe organic layer, decompress and removal the solvent, and the productwas obtained by purification; (7) Put the product obtained in (6) in aflask. NaOH solution was added into the product and stirred at roomtemperature; (8) After mixing the product in (7) with acid solution, theproduct in above (4) was added, the mixture was heated to obtain theplatinum compound of the present invention.
 15. The preparation methodsfor any platinum compound in claim 6 including the following steps: (1)Potassium chloroplatinite was added into water and the mixture wasstirred at room temperature; potassium iodide was dissolved by water andthen added into above solution to react away from light in water bathunder nitrogen charging condition; (2) After Bidentate ammonia NH₂—X—NH₂was dissolved by water, then it was added dropwise into the reactionmixture obtained in (1) to react in water bath; yellow deposit in greatquantity was afforded; after cooling down the mixture below roomtemperature, bidentatediiodo diamine platinum (II) was obtained bysuction filtration and washing; (3) Ag2SO4 was added in water and thenstirred; the above diiodo diamine platinum (II) was added into thereaction mixture and then water was added; the mixture was stirred inwater bath condition away from light and nitrogen is charged; dihydroldiamine platinum (II).sulfate was obtained by suction filtration; (4)Putting diethyl malonate, Br—R₃—Br, K₂CO₃ and tetrabutylammonium bromideinto a flask, the mixture was heated and stirred; after removal of solidby suction and washing, filtrate was washed and dried over MgSO4;distillate was collected in vacuo after removal of solvent; (5)Br—R₃-diethyl malonate was put into a flask, then anhydrous K₂CO₃ wasadded in and stirred with acetonitrile; R₁—NH—R₂ or R₁—N(R₀)—R₂ wasadded into reaction mixture; the mixture was stirred and heated; Afterfiltering out insoluble substance of the mixture, the filtrate waspumped dry and residue was dissolved in organic solvent and washed withaqueous solution; after dry the organic layer, decompress and removalthe solvent, and the product was obtained by purification; (6) Put theproduct obtained in (5) in a flask. NaOH solution was added into theproduct and stirred at room temperature; (7) After treating the productin (6) with acid solution, the product in above (3) was added, themixture was heated to obtain the platinum compound of the presentinvention.
 16. The use of any compounds in claim 1, theirpharmaceutically acceptable salts, their solvates, their stereoisomers,their prodrugs or the pharmaceutically compositions in claim 10 forpreparing the compounds for the treatment of cell proliferationdiseases.
 17. The use according to claim 16, wherein the cellproliferation diseases are preferably cancers.
 18. The use according toclaim 17, wherein the cancers are selected from breast cancer, lungcancer, colon cancer, gastric cancer, esophagus cancer, ovarian cancer,osteosarcoma, cervical cancer, bladder cancer, liver cancer, cerebroma,prostate cancer, or melanoma.
 19. A kit, including the pharmaceuticallycompositions in claim 10 and instructions.
 20. The kit according toclaim 19, which may comprise one or more other drugs for the treatmentof cancers.
 21. A method for the treatment of cell proliferationdiseases, comprising administering any drug in claim 1 to patients. 22.A method according to claim 21, wherein the cell proliferation diseasesare cancers.